EP1191028B1 - Composes tricycliques presentant une jonction spiro - Google Patents

Composes tricycliques presentant une jonction spiro Download PDF

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EP1191028B1
EP1191028B1 EP00940912A EP00940912A EP1191028B1 EP 1191028 B1 EP1191028 B1 EP 1191028B1 EP 00940912 A EP00940912 A EP 00940912A EP 00940912 A EP00940912 A EP 00940912A EP 1191028 B1 EP1191028 B1 EP 1191028B1
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group
compound
nonane
diaza
formula
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EP1191028A4 (fr
EP1191028A1 (fr
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Hidemitsu Mochida Pharmaceutical Co. Ltd NISHIDA
Fumihiko Mochida Pharmaceutical Co. Ltd. SAITOH
Kousuke Mochida Pharmaceutical Co. Ltd. Harada
Ikuya Mochida Pharmaceutical Co. Ltd. Shiromizu
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Mochida Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96433—Serine endopeptidases (3.4.21)
    • G01N2333/96441—Serine endopeptidases (3.4.21) with definite EC number
    • G01N2333/96444—Factor X (3.4.21.6)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • This invention relates to orally administrable tricyclic compounds having spiro union or its salts thereof that are useful as pharmaceuticals, particularly as an inhibitor of activated blood coagulation factor X (hereunder referred to as FXa), and which exhibit potent anticoagulation action.
  • FXa activated blood coagulation factor X
  • This invention is illustrated by a drug designing method involving molecular design for creating a compound, which exhibits inhibitory activity for FXa.
  • ischemic heart diseases and other pathology of heart and blood vessels are increasing year after year.
  • increase of vascular occlusive diseases such as myocardial infarction, cerebral thrombosis, pulmonary embolism, and peripheral arterial and venous occlusive disease is increasing each year and treatment of such diseases has become a serious social issue.
  • anticoagulation therapy has been playing an important role in internal medicine together with anti-platelet therapy and thrombolytic therapy.
  • safety that permits long-term drug administration and the development of a positive and appropriate anticoagulant activity are essential.
  • anticoagulants such as warfarin and heparin have been used in order to prevent and treat thrombosis due to hypercoagulability.
  • Warfarin is extensively used in the world as the solo peroral anticoagulant.
  • concentration range for the development of efficacy is narrow and yet it takes long to develop efficacy and the half-life in blood is as long as 36 hours; what is more, for several reasons such as the great individual difference of effective dose, it is difficult to control the anticoagulability of warfarin (N. Eng. J. Med.
  • warfarin also has many other side effects such as nausea, vomiting, diarrhea, and alopecia; thus, warfarin is a drug that involves considerable difficulty in clinical use.
  • heparin is extensively used in the world as an intravenously administrable anticoagulant. However, since it is a direct inhibitor of thrombin, heparin has a high risk of bleeding and needs as frequent monitoring as warfarin; what is more, due to its characteristics based on the mechanism of action, adequate coagulation inhibiting effect is not expected at a lowered antithrombin III level; thus, heparin is a drug that involves considerable difficulty in clinical use. In view of such situation, improved anticoagulants have been desired that has none of the defects inherent in warfarin and heparin.
  • the blood coagulation cascade is a chain reaction involving limited protein hydrolysis triggered by activation of the extrinsic coagulation cascade or the intrinsic coagulation cascade, and once the cascade is activated, the reaction is amplifies like an avalanche. Since the final stage of the blood coagulation cascade is thrombin-mediated conversion of fibrinogen to fibrin, efforts have recently been made to develop thrombin inhibitors; however, drugs that directly inhibit thrombin are known to increase the risk of bleeding. In addition, they have low bioavailability in oral administration; therefore no thrombin inhibitor, which can be orally administered, has been introduced into market.
  • FXa is a key enzyme, which is located in the upstream of the thrombin in the coagulation cascade, and also at the point of convergence between the extrinsic and the intrinsic coagulation cascade.
  • One molecule of FXa is known to produce about a hundred molecules of thrombin per minute. Therefore, an FXa inhibitor can potentially inhibit the coagulation cascade more efficiently than a thrombin inhibitor (Thrombosis Research, vol. 19, pages 339-349, 1980; Mebio vol. 14, No. 8, 1997).
  • FXa inhibitor Compounds having an aminoheterocyclic group typified by 1-(4-pyridyl)piperidin-4-yl group can be used as FXa inhibitor; for example, disclosed in prior art references including WO96/10022, WO97/28129, WO97/29104, WO98/21188, WO98/54164, WO99/06371, and WO99/09027.
  • the desired pharmacological activity is not the sole requirement.
  • Another requirement is that strict criteria be met in various aspects including absorption, distribution, metabolism and excretion, and the like.
  • the drugs are required to pass various examinations for drug interaction, desensitization or tolerance, absorption from digestive tract in the oral administration, transfer rate to small intestine, absorption rate and first pass effect, organ barrier, protein binding, induction of drug metabolizing enzyme, excretion pathway and clearance from body, administration method (site, method, and purpose of administration), and the like, and a drug meeting all such requirements are seldom discovered.
  • the anticoagulants also share such general challenge of the drug development.
  • condition of the binding between the FXa and the FXa inhibitor has great significance.
  • active site of the FXa is formed in the structure characteristic to a chymotrypsin-like serine protease.
  • the active center of a serine protease is formed from a plurality of pockets called subsites, and it is known that substantially all of the inhibitors which do not form covalent bond with Ser195 residue bind to these pockets.
  • S1 pocket is believed to be the most important in the serine protease in the binding with the substrate, or in the development of the substrate selectivity.
  • S1 site is also believed to be the most important in the serine protease inhibitor for the development of the inhibitory activity and the enzyme selectivity.
  • the residue which is generally believed to be the most important for the substrate specificity in the S1 pocket is the residue corresponding to chymotrypsin No. 189, and FXa has Asp (Aspl89) as this residue and the inside of the pocket is believed to be negatively charged.
  • the substrate specificity of the entire enzyme is determined by structural difference of the subsite such as S3 pocket in addition to the structural difference of S1, and designing of an inhibitor selective for FXa can be accomplished by using such structural difference.
  • amidino group is bound to S1 pocket of the FXa, and in particular, Asp189 and the amidino group are firmly bound to each other by electrostatic interaction and hydrogen bonds. This is the binding manner commonly known in trypsin inhibitors and thrombin inhibitors.
  • DX-9065a and FX-2212a are insufficient in their efficacy in oral administration, and there was also apprehension for the side effects induced by amidino group and guanidino group. In the meanwhile, it has not been even found out for the FXa inhibitors having other structure whether such X-ray crystallographic analysis is possible, and the binding state with the FXa was not at all found out.
  • an anticoagulant drug which exhibits high safety and excellent effectivity, and which is easy to use.
  • an anticoagulant which can be orally administered to human and other mammals, and in particular, which can be readily used in clinical practice, and which has realized at least one of avoidance of interaction with other drugs, reduced side effects including reduced risk of bleeding, improved dose response, and the like.
  • the inventors of the present invention conducted an intensive study in order to solve the problems as described above and to provide a compound which has excellent FXa inhibitory action, and found that the compound of formula (I) having spiro skeleton exhibits remarkably excellent FXa inhibitory action.
  • the present invention has been completed on the bases of such finding.
  • the inventors of the present invention also succeeded in producing the crystal of the complex of the FXa inhibitor of the present invention and the FXa, and found an important pharmacophore useful in discovering the FXa inhibitor of the type which is different from DX-9065a and the like through the analysis of such crystal.
  • the present invention has been completed also on the basis of such finding.
  • the present invention relates to a tricyclic compound having spiro union as represented by formula (I) which will be described below, pharmaceutical compositions, and uses thereof for the preparation of a medicament for the prophylactic and/ or therapeutic inhibition of the FXa in a mammal.
  • C 1-6 for example, means that "the group is a straight chain or branched group containing 1 to 6 carbon atoms” unless otherwise noted. In the case of a cyclic group, “C 1-6 “ denotes "the number of ring member carbon atoms”.
  • the compound of formula (I) and the compound of formula (I' ) according to the present invention are not particularly limited for their molecular weight.
  • the molecular weight is preferably up to 1000, and more preferably up to 700 (and otherwise stated, the total number of carbon atoms constituting the compound is less than 40).
  • Such limitation of molecular weight is routinely employed for identifying the structure of the compound as a major limiting factor in addition to the pharmacologically characteristic basic skeleton in recent drug design.
  • the molecular weight is preferably limited to the range of up to 1000 when oral absorptivity of the drug is taken into consideration.
  • the compound used in the aspects [18-f] to [18-h] is preferably the one having the FXa inhibitory activity in terms of IC 50 of up to 0.5 ⁇ M, more preferably up to 0.1 ⁇ M, and most preferably up to 0.01 ⁇ M.
  • the compound of the present invention may include an asymmetric carbon, and the compound of the present invention may be a mixture or an isolation product of geometric isomer, tautomer, optical isomer or other stereoisomer. Isolation or purification of such stereoisomer may be accomplished by those skilled in the art using any of the techniques commonly used in the art, for example, by optical resolution using preferential crystallization or column chromatography, or by asymmetric synthesis.
  • the compound (I) of the present invention may be in the form of an acid addition salt, and depending on the type of the substituent, the compound (I) may also be in the form of a salt with a base.
  • Such salt is not particularly limited as long as the salt is a pharmaceutically acceptable salt, and exemplary salts include acid addition salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or other mineral acid; acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, formic acid, malic acid, tartaric acid, citric acid, mandelic acid, or other organic carboxylic acid; methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, 2-hydroxy ethanesulfonic acid, or other organic sulfonic acid; or aspartic acid, glutamic acid,
  • the salts of the compound of the present invention also include mono-salts, di-salts, and tri-salts. Still further, the compound of the present invention may simultaneously form an acid addition salt and a salt with base depending on the type of the substituent on the side chain.
  • the present invention also includes hydrates of the compound (I) as well as pharmaceutically acceptable solvates and crystalline polymorphic forms of the compound (I). It should also be taken for granted that the present invention is by no means limited to the compounds mentioned in the Examples as described below, and all of the tricyclic compounds having the spiro union as represented by formula (I) and their pharmaceutically acceptable salts are within the scope of the present invention.
  • the compounds of the present invention represented by formula (I) and the related compounds can be produced by the production processes as described below.
  • W in the production process represents the leaving group or the group convertible into the leaving group as described above.
  • J represents a thiol protective group such as p-methoxybenzyl group.
  • P 1 and P 2 in the intermediate compounds of formulae (Ik) to (IIIk-9) marked with "k” independently represent hydrogen atom or a protective group of the imino group (-NH-).
  • Exemplary protective groups of the imino group (-NH-) include aralkyl groups such as benzyl group; acyl groups such as acetyl group; and alkoxycarbonyl groups such as benzyloxycarbonyl group, and t-butoxycarbonyl group.
  • deblocking may be accomplished by adequately selecting the type of the protective groups or the conditions of the deblocking to independently or simultaneously remove the protective groups, and if necessary, the protective groups and the like can also be reintroduced.
  • reaction temperature is in the range of -78°C to the solvent-reflux temperature
  • reaction time is the time sufficient for required progress of the reaction.
  • Solvent which is not involved in the reaction may be any of the aromatic hydrocarbon solvents such as toluene and benzene; polar solvents such as water, methanol, DMF, and DMSO; basic solvents such as triethylamine and pyridine; halogen solvents such as chloroform, methylene chloride, and 1,2-dichloroethane; ethereal solvent such as diethylether, tetrahydrofuran, and dioxane; and mixed solvents thereof; and the solvent used may be adequately selected depending on the reaction conditions.
  • Base may be any of inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and sodium hydride; or organic bases such as triethylamine, pyridine, N,N-dialkylaniline, and lithium diisopropylamide; and acid may be any of mineral acids such as hydrochloric acid, and sulfuric acid; organic acids such as methanesulfonic acid and p-toluenesulfonic acid.
  • the base and the acid are not necessarily limited to those mentioned above.
  • the compounds represented by formula (I) and formula (Ik) which are the compounds of the present invention or their salts may be synthesized from the compounds represented by formula (II), formula (IIk), formula (III), formula (IIIk), formula (111-3), formula (IIIk-4), formula (IIIk-6), formula (IV), formula (V), or formula (VI) or their salts which can be readily produced from known or commercially available compounds, by ⁇ Production process 1>, ⁇ Production process 2>, ⁇ Production process 3>, or ⁇ Production process 4>.
  • the compound represented by the formula: (wherein A, B, D, Q, T, X, Y, Z, l, m, and n, and substitution of each alkylene chain are as defined above; and r is 1) or its salt may be produced by the process as described below.
  • reaction preferably by using toluene for the solvent in the presence or absence of an acid catalyst, and preferably, in the presence of p-toluenesulfonic acid.
  • the reaction may be promoted at a temperature in the range of 0°C to the solvent reflux temperature, and preferably at the solvent reflux temperature for a time sufficient for the progress of the required reaction, and preferably for 2 to 6 hours to produce the compound represented by formula (I-a) or its salt.
  • interconversion between carbonyl group and thiocarbonyl group or conversion into methyelene group may be accomplished, if necessary, by a known process, for example, by the process described in "Shinjikkenkagakukouza 14 Synthesis and Reaction of Organic Compounds [III]", page 1817, 1978, Maruzen.
  • the compound When Y is O (oxygen atom), the compound may be produced, for example, by the production process as described below.
  • a compound represented by the formula (II-1) or its salt which is commercially available or readily derived from a commercially available compound may be reacted in accordance with the known process described in documents (for example, "Shinjikkenkagakukouza 14 Synthesis and Reaction of Organic Compounds [III]", page 1455, 1978, Maruzen) to produce the compound represented by formula (II-2) or its salt.
  • the compound represented by formula (11-2) or its salt obtained in ⁇ Step II-1-1> may be then reduced in accordance with the known process described in documents (for example, "Shinjikkenkagakukouza 14 Synthesis and Reaction of Organic Compounds [III]", page 1332, 1978, Maruzen) to produce the compound represented by formula (II-a) or its salt.
  • a compound represented by formula (II-1) or its salt may be reacted in accordance with the known process described in documents (for example, "Shinjikkenkagakukouza 14 Synthesis and Reaction of Organic Compounds [I]", page 594, 1977, Maruzen) to produce the compound represented by formula (II-3) or its salt.
  • the compound represented by formula (II-3) or its salt obtained in ⁇ Step II-2-1> may be then reacted in accordance with the known process described in documents (for example, Synthesis, page 629, 1984) to produce the compound represented by formula (II-a) or its salt.
  • the compound When Y is S (sulfur atom), the compound may be produced, for example, by the production process as described below.
  • a compound represented by the formula (II-4) (wherein R is a hydrocarbon group as typically represented by C 1-6 alkyl groups such as methyl, ethyl, propyl, and t-butyl and aralkyl groups such as benzyl group) or its salt which is commercially available or readily derived from a commercially available compound may be reacted in accordance with the known process described in documents (for example, JP09510700) to produce the compound represented by formula (II-5): (wherein R is the same as R in (II-4); J is a protective group such as p-methoxybenzyl group) or its salt.
  • the compound represented by formula (II-6) or its salt obtained in ⁇ Step II-3-2> may be then reduced in accordance with the known process described in documents (for example, "Shinjikkenkagakukouza 14 Synthesis and Reaction of Organic Compounds [III]", page 1332, 1978, Maruzen) to produce the compound represented by formula (II-7) or its salt.
  • the compound When Y is O (oxygen atom), the compound may be produced, for example, by the production process as described below.
  • a compound represented by formula (II-8): or its salt which is commercially available or readily derived from a commercially available compound may be reacted in accordance with the known process described in documents (for example, "Shinjikkenkagakukouza 14 Synthesis and Reaction of Organic Compounds [I]", page 331, 1977, Maruzen) to produce a reactive derivative represented by formula (II-9) or its salt.
  • the compound represented by formula (II-9) or its salt obtained in ⁇ Step II-4-1> may be then reacted with an active methylene compound such as ethyl cyanoacetate, ethyl nitroacetate, ethyl malonate monoamide or ethyl cyanopropionate in a solvent which is not involved in the reaction in the presence of a base to produce the compound represented by formula (II-10) (wherein E represents nitro group, cyano group, or amide group; and R is the same as R defined in formula (II-4)) or its salt.
  • an active methylene compound such as ethyl cyanoacetate, ethyl nitroacetate, ethyl malonate monoamide or ethyl cyanopropionate
  • the compound represented by formula (II-10) or its salt obtained in ⁇ Step II-4-2> may be then reduced in accordance with the known process described in documents (for example, "Shinjikkenkagakukouza 14 Synthesis and Reaction of Organic Compounds [III]", page 1332, 1978, Maruzen) to produce the compound represented by formula (II-c) or its salt.
  • the compound When Y is imino group (-NH-), the compound may be produced, for example, by the production process as described below.
  • the compound represented by formula (II-c) or its salt obtained in ⁇ Step II-4-3> may be reacted with a phosphorus compound such as triphenylphosphin or tributylphosphin and an azodicarboxylate as typically represented by diethyl azodicarboxylate (DEAD) in a solvent which is not involved in the reaction to activate the hydroxyl group, and the resulting product may be reacted with phthalimide to produce the compound represented by formula (II-11) or its salt.
  • a phosphorus compound such as triphenylphosphin or tributylphosphin
  • an azodicarboxylate as typically represented by diethyl azodicarboxylate (DEAD)
  • DEAD diethyl azodicarboxylate
  • the compound represented by formula (II-11) or its salt obtained in ⁇ Step II-5-1> may be then reacted for deblocking to produce the compound represented by formula (II-d) or its salt.
  • the compound When Y is imino group (-NH-), the compound may be produced, for example, by the alternative production process as described below.
  • the compound represented by formula (11-12) or its salt obtained in ⁇ Step II-6-1> may be reduced in accordance with ⁇ Step II-1-2> to produce the compound represented by formula (II-e) or its salt.
  • the compound represented by formula (II-1) or its salt may be reacted in accordance with the known process described in documents (for example, DE4405140, Scheme 1 (Reaction i)) to produce the compound represented by formula (II-12) or its salt.
  • the substituent may be introduced into the alkylene chain, for example, by using a commercially available compound having the corresponding substituent for the starting material (II-1) or (II-8); by introducing the corresponding substituent in the starting material by the process commonly used in the synthesis; by converting the active methylene compound of ⁇ Step II-4-1> to an adequately substituted derivative before the reaction with the methylene compound; by reducing the cyano group in (II-2) or (II-4) to amide group, and converting and/or modifying the carbonyl group as desired; or if necessary, by directly introducing the substituent into the compound represented by formula (II).
  • D may be introduced in accordance with the process employed for the synthesis of D as described below.
  • a compound represented by formula (III-1): (wherein n is 1 or 2) or its salt which is commercially available or readily derived from a commercially available compound, and a compound represented by formula (III-2): W-T-Q (wherein W, Q, and T are as described above) or its salt which is commercially available or readily derived from a commercially available compound may be fused to produce the compound represented by formula (III-3) or its salt.
  • T is sulfonyl group and W is chlorine atom
  • the reaction may be carried out in methylene chloride in the presence of triethylamine at a temperature in the range of 0°C to room temperature, and preferably, at room temperature for 2 to 12 hours.
  • the compound represented by formula (111-3) or its salt obtained in ⁇ Step III-1-1> may be reacted with an alkylating agent represented by formula (III-4) in a solvent which is not involved in the reaction in the presence of a base to produce the compound represented by formula (III) or its salt.
  • the compound represented by formula (III-5) or its salt obtained in ⁇ Step III-2-1> is condensed with the compound represented by formula (III-2) or its salt in accordance with the procedure of ⁇ Step III-1-1> to produce the compound represented by formula (III) or its salt.
  • carbonyl group in the formula (III) may be protected if necessary, and the protective group may be removed at an adequate stage.
  • substituent may be introduced at the alkylene chain, for example, by using a commercially available compound having the corresponding substituent for the starting material (III-1) or (III-4); or by introducing the corresponding substituent in the starting material by the known process described in the documents.
  • the compound represented by: (wherein A, B, Q, T, X, Y, Z, l, m, and n are as defined above) or its salt may be produced by the process as described below.
  • the compound represented by formula (II) produced by the process described in ⁇ Production process 1> or its salt and the compound represented by formula (IV) or its salt which is commercially available or readily derived from a commercially available compound wherein A, B, X, Y, l, and m, and substitution of each alkylene chain are as defined above; and R is hydrogen atom, a C 1-6 alkyl, a C 1-6 alkoxy, or a C 1-6 alkyl group optionally substituted with hydroxyl or a halogen atom (and in particular, methyl group or ethyl group); or the two R may together represent a C 1-6 alkyl, a C 1-6 alkoxy, a C 2-4 alkylene group optionally substituted with hydroxyl or a halogen atom (in particular, 1,2-ethylene group or 1,3-propylene group)) may be reacted in accordance with the procedure of ⁇ Production process 1> to produce the compound represented by formula (V) or its salt.
  • W is a halogen atom, hydroxyl group, or an alkoxy group in the compound represented by formula (III-3) or its salt
  • amidation in normal peptide is carried out.
  • W is hydroxyl group
  • a phenol such as 2,4,5-trichlorophenol, pentachlorophenol, 2-nitrophenol, or 4-nitrophenol
  • a N-hydroxy compound such as N-hydroxysuccinimide, N-hydroxy-5-norbornene-endo-2,3-dicarboxyimide or N-hydroxypiperidine is condensed in the presence of a condensing agent such as N,N-dicyclohexylcarbodiimide for conversion into active ester form, and allowed for reaction.
  • reaction may be conducted after producing a mixed acid anhydride by reacting with a halogenated acyl compound such as isobutylchloroformate.
  • a halogenated acyl compound such as isobutylchloroformate.
  • the reaction may be also promoted by using a peptide condensation reagent such as N,N-dicyclohexylcarbodiimide, diphenylphosphoric acid azide or diethyl cyanophosphate alone.
  • the compound represented by formula (III-3) may be activated by using a phosphorus compound such as triphenylphosphin or tributylphosphin and an azodicarboxylate typically represented by diethyl azodicarboxylate, and then reacted in a solvent which is not involved in the reaction.
  • a phosphorus compound such as triphenylphosphin or tributylphosphin
  • an azodicarboxylate typically represented by diethyl azodicarboxylate
  • the compound represented by formula (VI) (wherein A, B, Q, T, X, Y, Z, l, m, and n, and substitution of each alkylene chain are as defined above; and R is the same as R defined in the compound represented by formula (IV)) or its salt obtained in ⁇ Step 2> may be then reacted in accordance with the known process described in documents (for example, JP09316059) in a solvent which is not involved in the reaction, and preferably by using toluene for the solvent, in the presence of an acid catalyst, and preferably in the presence of p-toluenesulfonic acid to produce a compound represented by formula (I-b) or its salt.
  • the reaction temperature is preferably in the range of 70°C to 80°C, and the reaction time is preferably in the range of 1 to 2 hours.
  • substituent Z interconversion between carbonyl group and thiocarbonyl group or conversion into methyelene group may be accomplished, if necessary, by a known process, for example, the process described in "Shinjikkenkagakukouza 14 Synthesis and Reaction of Organic Compounds [III]", page 1817, 1978, Maruzen. (In the formula, A, B, Q, T, X, Y, Z, l, m, and n are as defined above)
  • the compound represented by formula (I-b): (wherein A, B, Q, T, X, Y, Z, l, m, and n are as defined above) or its salt produced in ⁇ Production process 2> may be reacted for reduction of the double bond in the formula to produce the compound represented by formula (I-a) or its salt.
  • Exemplary reduction processes include reduction by a metal or a metal salt such as sodium, calcium and aluminum; reduction by a metal hydride such as diisopropyl aluminum hydride; and reduction by a metal hydride complex such as sodium borohydride; electrophilic reduction by diborane or substituted borane; and catalytic hydrogenation using a metal catalyst.
  • the reaction solvents used is a solvent which is not involved in the reaction, for example, tetrahydrofuran, toluene, methylene chloride, or methanol, or a mixture thereof, and the reaction is conducted at a temperature of -78°C to reflux temperature for a time sufficient for required progress of the reaction.
  • A, B, D, Q, T, X, Y, Z, l, m, n, and r are as defined above
  • the compound represented by formula: (wherein D, P 1 , P 2 , Y, Z, l, m, n, and r, and substitution of each alkylene chain are as defined above) or its salt may be produced by the process as described below.
  • the compound represented by formula (Ik) or its salt may be produced also by another process as described below.
  • the reaction may be promoted in accordance with ⁇ Step 1> by using a reaction solvent which is described in ⁇ Production process 1>, or alternatively, a halogen solvent such as methylene chloride, chloroform, or 1,2-dichloroethane, the preferred being chloroform, and there is produced a compound of formula (Ik') (wherein D, P 1 , P 2 , W, Y, Z, l, m, and n, and substitution of each alkylene chain are as defined above; and r is 1).
  • a reaction solvent which is described in ⁇ Production process 1>
  • a halogen solvent such as methylene chloride, chloroform, or 1,2-dichloroethane, the preferred being chloroform
  • the compound represented by formula (Ik') or its salt produced in ⁇ Step 2> may be then condensed in accordance with ⁇ Production process 2> ⁇ Step 2> to produce the compound represented by formula (Ik) or its salt.
  • the compound represented by formula (IIk) or its salt may be produced in accordance with the production process of ⁇ Production process 1> ⁇ formula (II)>.
  • the compound represented by formula (IIIk) or its salt may be produced in accordance with the production process of ⁇ Production process 1> ⁇ formula (III)>.
  • the compound represented by formula (IIIk) may be produced also by different processes as described below.
  • the compound represented by formula (IIIk-2) or its salt obtained in ⁇ Step IIIk-1-1> may be then reacted for normal introduction of the protective group P 2 into the imino group (-NH-) to produce the compound represented by formula (IIIk-3) or its salt.
  • the compound represented by formula (IIIk-3) or its salt obtained in ⁇ Step IIIk-1-2> may be then reacted in a solvent which is not involved in the reaction for oxidation by manganese dioxide; chromic acid oxidation by chromium oxide (VI) or dichromate; oxidation by lead tetraacetate; oxidation by oxygen; oxidation by activated DMSO; oxidation by high valence iodine typically represented by Dess-Martin reagent; oxidation by halogen compound such as hypohalogenous acid or its salt to produce the compound represented by formula (IIIk) or its salt.
  • the compound represented by formula (III-1) or its salt may be reacted by ⁇ Step IIIk-1-2> and ⁇ Step IIIk-1-1> through the compound represented by formula (IIIk-4) or its salt to produce the compound represented by formula (IIIk-3) or its salt.
  • the compound represented by formula (IIIk-2) or its salt may be reacted by ⁇ Step IIIk-1-3> and ⁇ Step IIIk-1-2> through the compound represented by formula (IIIk-5) or its salt to produce the compound represented by formula (IIIk) or its salt.
  • the compound represented by formula (IIIk-6) or its salt may be reacted in accordance with ⁇ Step IIIk-1-1> and ⁇ Step IIIk-1-2> through the compound represented by formula (IIIk-9) or its salt to produce the compound represented by formula (IIIk-3) or its salt.
  • the compound of formula (IIIk-9) may be oxidized in accordance with ⁇ Step IIIk-1-3> to produce the compound represented by formula (IIIk-7) or its salt.
  • a compound having -T-Q instead of the -P 2 for example, a compound of formula (IIIk-6) wherein -P 2 is -T-Q, or a compound of formula (IIIk-4) wherein -P 2 is -T-Q may be used in accordance with the alternative process as described above to produce the compound represented by formula (III) or its salt.
  • P 1 or P 2 may be independently deblocked at the most adequate stage for subsequent conversion into the A-B or the T-Q. Conversion into the A-B and the T-Q is described later.
  • the compound represented by formula (I-a) or its salt wherein P 1 - is A-B-, and -P 2 is -T-Q can be produced by the production of the compound represented by formula (I-a'): (wherein A, B, D, Q, T, X, Y, l, m, n, and W, and substitution of each alkylene chain are as defined above; r is 1; and Z represents carbonyl group or thiocarbonyl group) or its salt followed by condensation.
  • the conversion of the substituents D, A-B, and T-Q may be carried out at any stage in the ⁇ Production process 1>, ⁇ Production process 2>, ⁇ Production process 3>, and ⁇ Production process 4>, or in the stage of the starting compound, or in any reaction stage of producing such starting compound.
  • the compound represented by formula (I-a-1) or its salt obtained in ⁇ Step D-1> is reacted with aqueous solution of sodium hydroxide, for example, in methanol at room temperature to produce the compound represented by formula (I-a-2): (wherein A, B, Q, T, X, and n, and substitution of each alkylene chain are as defined above) or its salt.
  • the compound wherein D' is -CH 2 OH or its salt may be reacted with a compound represented by formula: R'-W in a solvent which is not involved in the reaction, and preferably, in the mixed solvent of methylene chloride and water in the presence of a base, and preferably, using sodium hydroxide in the presence or absence of a phase transfer catalyst such as quaternary ammonium salt or crown ether, and preferably, in the presence of benzyltriethylammonium chloride at a temperature of -78°C to reflux temperature, and preferably, at 0°C for a time sufficient for the required progress of the reaction, and preferably, for 2 hours for conversion into the compound wherein D is -CH 2 -OR' or its salt.
  • a solvent which is not involved in the reaction and preferably, in the mixed solvent of methylene chloride and water in the presence of a base, and preferably, using sodium hydroxide in the presence or absence of a phase transfer catalyst such as quaternary ammoni
  • the compound wherein D' is -CH 2 OH or its salt is reacted with a compound represented by formula: R'-OH activated by using a phosphorus compound such as triphenylphosphin or tributylphosphin and an azodicarboxylate as typically represented by diethyl azodicarboxylate(DEAD) in a solvent which is not involved in the reaction for conversion into the compound wherein D is -CH 2 -OR' or its salt.
  • a phosphorus compound such as triphenylphosphin or tributylphosphin
  • an azodicarboxylate as typically represented by diethyl azodicarboxylate(DEAD) in a solvent which is not involved in the reaction for conversion into the compound wherein D is -CH 2 -OR' or its salt.
  • the compound wherein D' is -CH 2 OH or its salt may be reacted with R"-CO-W in a solvent which is not involved in the reaction in the presence or absence of a base or in the presence or absence of an acid for conversion into the compound wherein D is -CH 2 -O-CO-R" or its salt.
  • the compound wherein D' is -CH 2 OH or its salt may be reacted with thionyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, or the like in a solvent which is not involved in the reaction in the presence or absence of a base or in the presence or absence of an acid for conversion into the compound wherein D' is -CH 2 -W or its salt.
  • the compound wherein D' is -CH 2 -W or its salt may be further reacted with an amine represented by HNR'R" (for example, HNR 6 R 7 and NR 6 R 7 are as defined above) in a solvent which is not involved in the reaction in the presence or absence of copper powder, copper oxide powder, or iron powder in the presence or absence of a base or in the presence or absence of an acid for conversion into the compound wherein D is -CH 2 -NR'R'' or its salt.
  • a metal such as copper, palladium, chromium, or bismuth may be employed for formation of a complex with the compound wherein D' is represented by -CH 2 -W in order to use the compound with a higher activity in the reaction.
  • the compound wherein D' is -CH 2 OH or its salt may be reacted with a phosphorus compound such as triphenylphosphin or tributylphosphin and an azodicarboxylate as typically represented by diethyl azodicarboxylate (DEAD) in a solvent which is not involved in the reaction to activate the hydroxyl group, and the resulting product may be reacted with the compound represented by formula: NHR'R" for conversion into the compound wherein D is -CH 2 -NR'R" or its salt.
  • a phosphorus compound such as triphenylphosphin or tributylphosphin and an azodicarboxylate as typically represented by diethyl azodicarboxylate (DEAD)
  • DEAD diethyl azodicarboxylate
  • R" is hydrogen in the resulting compound wherein D is -CH 2 -NR'R" or its salt
  • the compound may be reacted with R'''-CO-W (wherein W is as defined above; and R''' is an optionally substituted C 1-6 alkyl group) in a solvent which is not involved in the reaction in the presence or absence of a base or in the presence or absence of an acid for conversion into the compound wherein D is -CH 2 -NR'-CO-R''' or its salt.
  • R'' is hydrogen in the resulting compound wherein D is -CH 2 -NR'R'' or its salt
  • the compound may be also alkylated with R'''-W (wherein R''' is an optionally substituted C 1-6 alkyl group) in a solvent which is not involved in the reaction in the presence or absence of a base or in the presence or absence of an acid for conversion into the compound wherein D is -CH 2 -NR'R''' or its salt.
  • R" is hydrogen in the resulting compound wherein D is -CH 2 -NR'R'' or its salt
  • the compound may be also reacted with a ketone or an aldehyde represented by formula: R d1 -CO-R d2 (wherein R d1 and R d2 are independently hydrogen atom, an optionally substituted C 1-6 alkyl group, a C 3-6 cycloalkyl group, or a five- or six-membered heterocyclic group containing at least one heteroatom selected from N, 0, and S, or d1, d2 and carbon atom of the ketone together form a five- or six-membered cyclic group which may contain at least one heteroatom selected from N, 0, and S) in a solvent which is not involved in the reaction in the presence of a reducing agent such as sodium borohydride, lithium aluminum hydride, or diisobutylaluminum hydride for reductive amination of the compound to thereby convert the compound into the compound
  • the compound wherein D' is -CH 2 OH or its salt may be reacted in a solvent which is not involved in the reaction for oxidation by manganese dioxide; chromic acid oxidation by chromium oxide (VI) or dichromate; oxidation by lead tetraacetate; oxidation by oxygen; oxidation by activated DMSO; oxidation by halogen compound such as hypohalogenous acid or its salt to thereby convert the compound into the compound wherein D is -CHO or its salt.
  • the compound wherein D' is -CH 2 OH or its salt may be reacted in a solvent which is not involved in the reaction for oxidation by manganese dioxide; chromic acid oxidation by chromium oxide (VI) or dichromate; oxidation by lead tetraacetate; oxidation by oxygen; oxidation by activated DMSO; oxidation by halogen compound such as hypohalogenous acid or its salt to thereby convert the compound into the compound wherein D is -CO 2 H or its salt.
  • the compound wherein D is -CO 2 H or its salt can be also produced by reacting the compound wherein D is -CHO or its salt synthesized in 1-4) for oxidation by manganese dioxide; chromic acid oxidation by chromium oxide (VI) or dichromate; oxidation by lead tetraacetate; oxidation by oxygen; oxidation by activated DMSO; oxidation by halogen compound such as hypohalogenous acid or its salt.
  • the compound wherein D is -CHO or its salt synthesized in 1-4) may be reacted with a nucleophilic reagent such as methyllithium or phenyllithium in a solvent which is not involved in the reaction for conversion into the compound wherein D is -CH(OH)R d3 or its salt.
  • a nucleophilic reagent such as methyllithium or phenyllithium in a solvent which is not involved in the reaction for conversion into the compound wherein D is -CH(OH)R d3 or its salt.
  • the resulting compound wherein D is -CH(OH)R d3 or its salt may be converted into the compound wherein D is -CH(OR')R d3 or its salt by the procedure similar to 1-1); into the compound wherein D is -CH(O-CO-R')R d3 or its salt by the procedure similar to 1-2); and into the compound wherein D is -CH(NR'R'')R d3 (wherein NR'R" is as defined above) or its salt by the procedure similar to 1-3).
  • the compound wherein D is -CH(OH)R d3 or its salt may be also converted into the compound wherein D is -CO-R d4 (wherein R d4 is an alkyl group adequately selected from for example R 15 ) by the procedure similar to 1-4).
  • a catalyst such as activated carbon-palladium to convert the compound into the compound wherein D is -CHR d4 -CHR d5 R d6 (wherein R d5 and R d6 are, for example, a C 1-6 alkyl group) or its salt.
  • a catalyst such as activated carbon-palladium in a solvent which is not involved in the reaction to convert the compound into the compound wherein D is -CH 2 -CHR d5 R d6 or its salt.
  • the compound wherein D is -CHO or its salt synthesized in 1-4) may be reacted with the amine represented by the formula: HNR'R" as described above in a solvent which is not involved in the reaction in the presence of a reducing agent such as sodium borohydride, lithium aluminum hydride, or diisobutylaluminum hydride for reductive amination to thereby convert the compound into the compound wherein D is -CH-NR'R" or its salt.
  • a reducing agent such as sodium borohydride, lithium aluminum hydride, or diisobutylaluminum hydride for reductive amination
  • the compound wherein D is -CO 2 H or its salt synthesized in 1-5) may be reacted with R'-OH (wherein R' is an optionally substituted C 1-6 alkyl group) in a solvent which is not involved in the reaction in the presence or absence of a condensing agent such as carbodiimidazole for conversion into the compound wherein D is -CO 2 R' or its salt.
  • R'-OH an optionally substituted C 1-6 alkyl group
  • the compound wherein D is -CO 2 H or its salt may also be reacted with thionyl chloride or the like for conversion into a compound wherein D is -COCl, and the compound may be then reacted with R'-OH for conversion into the compound wherein D is -CO 2 R' or its salt.
  • the compound wherein D is -CO 2 H or its salt synthesized in 1-5) may be reacted with NHR'R" (as defined above) in a solvent which is not involved in the reaction in the presence or absence of a condensing agent such as carbodiimidazole for conversion into the compound wherein D is -CO-NR'R" or its salt.
  • the resulting compound wherein D is -CO-NR'R" or its salt may be reacted with a reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride to convert the compound into the compound wherein D is -CHO or its salt.
  • the resulting compound wherein D is -CO-NR'R" or its salt may be also reacted with a reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride to convert the compound into the compound wherein D is -CH 2 -NR'R'' or its salt.
  • a reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride
  • the compound wherein D is -CO 2 H or its salt synthesized in 1-5) may be reacted with a nucleophilic reagent such as methyllithium or phenyllithium in a solvent which is not involved in the reaction for conversion into the compound wherein D is -CO-R or its salt.
  • a nucleophilic reagent such as methyllithium or phenyllithium in a solvent which is not involved in the reaction for conversion into the compound wherein D is -CO-R or its salt.
  • the reaction with the nucleophilic reagent may be accomplished by using the compound wherein D is -CO 2 R' or its salt obtained in 3-1) or the compound wherein D is -CO-NR'R'' or its salt obtained in 3-2).
  • the substituent B or T when the substituent B or T is carbonyl group, the substituent may be derived by reaction with A-CO-W or Q-CO-W in accordance with the procedure described in 1-2) in a solvent which is not involved in the reaction in the presence or absence of a base or in the presence or absence of an acid.
  • the substituent may be derived by condensation using A-CO 2 H or Q-CO 2 H as described in 3-2).
  • the substituent B or T is -S(O) z -
  • the substituent may be derived by reaction with A-S(O) z -W or Q-S(O) z -W in accordance with the procedure described in 1-2) in a solvent which is not involved in the reaction in the presence or absence of a base or in the presence or absence of an acid.
  • the substituent B or T is an optionally substituted C 1-2 alkylene group
  • the substituent may be derived by converting the hydroxyl moiety of the corresponding alcohol form into a leaving group followed by nucleophilic substitution in accordance with the procedure described in 1-3); by using reductive amination of the corresponding aldehyde forms shown in 2-3); or by reducing the bond formed through the carbonyl as described above.
  • the substituent B When the substituent B is single bond, the substituent may be derived by using A-W through coupling reaction using the metal as described in 1-3); or by reacting the compound with an organic base such as triethylamine or diisopropylethylamine or an inorganic base such as potassium carbonate or sodium hydroxide in a polar solvent such as DMF, 2-ethoxyethanol, ethanol, or water at solvent reflux temperature or by heating in a sealed tube.
  • an organic base such as triethylamine or diisopropylethylamine or an inorganic base such as potassium carbonate or sodium hydroxide
  • a polar solvent such as DMF, 2-ethoxyethanol, ethanol, or water at solvent reflux temperature or by heating in a sealed tube.
  • geometric isomer, tautomer, optical isomer and other stereoisomers may be present for the compound of the present invention when X is methine carbon or when substituent D is present.
  • isomers and mixtures thereof are within the scope of the present invention. Isolation or purification of such stereoisomer may be accomplished by any of the techniques commonly used in the art, for example, recrystalization and various chromatographic processes. It is also possible to separately produce such isomer by asymmetric synthesis.
  • the pharmacophore illustrating the present invention is the one which has been described in the seventeenth aspect of the present invention, and more specifically, the one described in detail in [17-a] to [17-e].
  • the use of such pharmacophore enables designing and/or screening of an inhibitor which selectively inhibits FXa by reversibly binding to the active site of the FXa to develop competitive inhibitory activity for the FXa.
  • a rapid evaluation of a large number of compounds will be enabled, and such evaluation will greatly increase the efficiency of the biological tests which require enormous expenditure and time.
  • Such evaluation will also enable to limit the number of compounds actually synthesized and greatly increase the efficiency of the synthetic process.
  • the compound should be capable of physically/structurally binding to the active site of the FXa.
  • the noncovalent bond between a protein and an inhibitor generally takes the form of electrostatic interaction, hydrogen bond, van der Waals interaction, or hydrophobic interaction.
  • the compound should be capable of taking the conformation which enables the compound to bind to the active site of the FXa.
  • An efficient designing and/or screening of the inhibitor is enabled by selecting the compound which meets such conditions and the pharmacophore illustrating the present invention.
  • the discovery of the FXa inhibitory compound which fulfills the factors as described above may be accomplished by utilizing information on the three-dimensional structure of the FXa in combination with various computer programs and databases.
  • a compound which exhibits FXa inhibitory activity can be detected by selecting the compounds which satisfy the pharmacophore illustrating the present invention by the method as described below; purchasing or synthesizing the compound; and evaluating the compounds for their FXa inhibitory activity by a standard method.
  • Low molecular weight compounds are docked in the active site of the FXa.
  • the three-dimensional structure of the FXa is disclosed by PDB, and the structure of the active site is available from PDB.
  • the docking may be accomplished by various computer programs.
  • Use of the computer database of the three-dimensional compounds enables a screening from several million to several ten millions of compounds as well as screening of the non-existing compounds.
  • the compounds exhibiting a binding mode which satisfy the pharmacophore illustrating the present invention are extracted. The binding mode can be confirmed by using various molecular graphics software programs.
  • Compounds having both hydrophobic moiety and basic moiety are first selected from the database, and it is also possible to preliminarily include the non-existing compounds in the database. Three-dimensional structure of the selected compounds of low molecular weight are then docked in the active site of the FXa, and the compounds exhibiting a binding mode which satisfy the pharmacophore illustrating the present invention are extracted.
  • the docking may be accomplished by various computer programs, and the binding mode can be confirmed by using various molecular graphics software programs.
  • Low molecular weight compounds are docked to each of the S1 pocket and the S3 pocket of the FXa, respectively, so that the pharmacophore for the illustration of the present invention is satisfied.
  • the compounds used may be those of the computer database of three-dimensional compounds or any compounds or their fragments.
  • the compound which was placed to the S1 pocket and the compound which was placed to the S3 pocket were connected by using an adequate skeleton which does not change relative spatial position. This process can also be accomplished by using various computer programs.
  • the designing and/or screening of the compounds as described above may be accomplished by using the so called molecular design-assisting integrated computer system such as Insight II, Cerius2, Sybyl, and their modules.
  • Insight II and Cerius2 are available from Molecular Simulations Inc., San Diego, CA, USA, and Sybyl is available from Tripos Inc., St. Louis, MO, USA.
  • computer programs with specialized functions are also useful in the processes of detecting the low molecular weight compounds which fit with the structure of the active site; detecting the adequate compounds which satisfies the pharmacophore; or docking the low molecular weight compounds to the structure of the active site. Exemplary such programs include those as described below.
  • the compound having FXa inhibitory activity may also be designed or searched by a process other than the compound designing/screening process described in the present invention or the computer systems.
  • an inhibitor which competitively binds to the active site of the FXa or its fragment may be identified by:
  • the inhibitor may be identified by providing a computer system with the three-dimensional structural information of the FXa molecule containing the active site defined by coordinates of Table A as described below; depicting the three-dimensional structure of the active site in the computer system; overlaying the three-dimensional structure of a test compound on the three-dimensional structure of the active site such that the three-dimensional structure of the test compound is arranged to meet all of the following conditions that:
  • drug design may be accomplished by conducting an evaluation on a computer by using the three-dimensional structural information of the FXa or its fragment for a compound which satisfies the following association conditions:
  • a more specific identification or molecular designing of the FXa inhibitor is enabled by adding the condition for the pharmacophore illustrating the present invention that interaction with the Tyr228 is mediated by the halogen atom, methyl group, or ethyl group (preferably chlorine atom or bromine atom) constituting a part of the hydrophobic moiety.
  • the identification or molecular designing of the FXa inhibitor may be accomplished by adding the condition that, in the interaction with the Tyr228, the centroid of the hydrophobic moiety and the centroid of the Tyr228 side chain is within the range of 6.9 to 7.9 ⁇ .
  • the identification or molecular designing of the FXa inhibitory compound may be accomplished by adding the condition that the pharmacophore also satisfies at least one of the following conditions 1) to 3):
  • the identification or molecular designing of the FXa inhibitor may be accomplished by adding the condition that all of the conditions 1) to 3) are satisfied.
  • the molecular designing of the FXa inhibitor may be accomplished by adding the means for suppressing alteration of the conformation of the cross-linking group described in the aspect [18-e].
  • the thus identified or designed compound may be obtained by purchasing or synthesizing the compound, and the compound may be subjected to the bioassay, for example, the one described in the Examples of the present invention to determine its specific pharmacological activities, for example, in vitro IC 50 .
  • the compound is the one having a FXa inhibitory activity of up to 1 ⁇ M in terms of IC 50 , and preferably, the one which was unknown at the time of the filing of the present invention.
  • the present invention is also directed to a pharmaceutical composition characterized by its inclusion as an effective component of at least one compound which has been identified or designed by the identification or drug designing method as described above, which has FXa inhibitory activity in terms of IC 50 determined by a bioassay of up to 1 ⁇ M, and which was (1) unknown at the time of the filing of the present invention or (2) known but whose biological activity was unknown at the time of the filing of the present invention.
  • a pharmaceutical composition characterized by its inclusion as an effective component of at least one compound which has been identified or designed by the identification or drug designing method as described above, which has FXa inhibitory activity in terms of IC 50 determined by a bioassay of up to 1 ⁇ M, and which was (1) unknown at the time of the filing of the present invention or (2) known but whose biological activity was unknown at the time of the filing of the present invention.
  • the present invention is also directed to a FXa inhibitor characterized by its inclusion as an effective component of at least one compound which has FXa inhibitory activity in terms of IC 50 determined by a bioassay of up to 1 ⁇ M, and which was (1) unknown at the time of the filing of the present invention or (2) known but whose biological activity was unknown at the time of the filing of the present invention.
  • FXa inhibitor characterized by its inclusion as an effective component of at least one compound which has FXa inhibitory activity in terms of IC 50 determined by a bioassay of up to 1 ⁇ M, and which was (1) unknown at the time of the filing of the present invention or (2) known but whose biological activity was unknown at the time of the filing of the present invention.
  • the preferred is the one having the FXa inhibitory activity in terms of IC 50 of up to 0.5 ⁇ M, more preferably up to 0.1 ⁇ M, and most preferably up to 0.01 ⁇ M.
  • the identification or designing of such compound may be accomplished by assuming that the compound has a partial structure comprising the spiro skeleton which is the structure wherein one or both of La and Lb have been removed from the general formula (I'), and then defining the residual Lb, the residual La, or the residual Lb and La.
  • Lb may be defined, for example, after assuming the group represented by A-B- of formula (I) as a particular La, and for example, after setting the condition of the aspect 10-d, 4), namely the condition that "La has an optionally substituted, five- to six-membered, aromatic monocyclic heterocyclic group" for the La, and in particular, after assuming that La comprises 4-pyridyl group.
  • La may be defined by assuming the group represented by -T-Q of formula (I) as a particular Lb, and preferably, by assuming that Lb comprises a group wherein Q is the one described in the aspect [1-1-d] and T is the one described in the aspect [1-8-b], and most preferably, p-halogenostylylsulfonyl group, 6-halogenonaphthalen-2-ylsulfonyl group, or 7-halogeno-2H-benzopyran-3-ylsulfonyl group, as will be understood from the foregoing description.
  • the pharmaceutical composition of the present invention should contain at least one compound represented by formula (I) or formula (I'), formula (V), formula (VI), formula (Ik), formula (I-a'), formula (I'), or formula (I'') (the definition which may be as defined above) as its effective component, and the composition may also contain a pharmacologically acceptable carrier.
  • the preferable compounds for the compound represented by formula (I) are the same as those described above.
  • compositions of the present invention possess a potent FXa inhibitory activity.
  • the compositions of the present invention are a potent FXa inhibitor, and more particularly, a specific FXa inhibitor, which does not inhibit other enzymes.
  • compositions of the present invention are also an orally administrable FXa inhibitor, and more specifically, an orally administrable specific FXa inhibitor.
  • the compounds of the present invention specifically inhibit activity of the FXa among the many serine proteases. To be more specific, it does not inhibit trypsin or chymotrypsin at all, nor do they inhibit thrombin, which is another serine protease in the blood coagulation cascade.
  • the compounds of the present invention solve the aforementioned problems associated with the use of the conventional thrombin inhibitors, for example, the tendency to cause bleeding.
  • the compounds of the present invention can be rapidly absorbed by the digestive tract after oral administration with no reduction in its activity by the absorption, and it also exhibit favorable absorption, distribution, metabolism, and excretion characteristics. Its value as an orally administrable agent is quite high.
  • compositions containing the compounds of the present invention can be used as preventives and/or therapeutics of diseases wherein an FXa inhibitor is useful.
  • compositions containing the compounds of the present invention cab also be used as an anticoagulant, and as preventives and/or therapeutics of diseases for which anticoagulant is useful.
  • such agents are effective in prevention and/or treatment of diseases caused by thrombus or embolism.
  • diseases include: diseases from ischemic cerebrovascular disorders such as cerebral thrombosis, brain infarction, cerebral embolism, transient cerebral ischemic attack (TIA) and cerebral vascular spasm after subarachnoid hemorrhage; Alzheimer's disease, cerebrovascular dementia, asymptomatic cerebrovascular disorder, disease associated with ischemic heart disease such as acute and chronic myocardial infarction, aftereffect after myocardial infarction, unstable angina pectoris, angina pectoris and coronary thrombolysis; thrombogenesis after artificial blood vessel or artificial valve replacement, reocclusion and restenosis after coronary artery bypass grafting, reocclusion and restenosis after PTCA or PTCA or stent placement, pulmonary infarction, lung thrombus/lung embolism, diseases associated with pulmonary vascular disorder (for example, drug-induced
  • prophilaxis of vascular endothelial cell injury associated with diabetes hypercoagulation associated with transplantation or activated protein C (APC) resistance, blood hypercoagulation associated with vascular disease, injury after operation, obesity, pregnancy, use of oral contraceptive, sustained depression, heparin induced thrombocytopenia, collagen disease (for example, antiphospholipid syndrome, polyarteritis, and systemic lupus erythematosus), Bechet's disease, ischemic reperfusion injury, cancer or the like, and toxemia in pregnancy.
  • APC activated protein C
  • the agents of the present invention are particularly adapted for use in prevention of embolism associated with atrial fibrillation/artificial valve or valvular heart disease, and preferably for prevention of onset of cerebral embolism, prevention of transient cerebral ischemic attack and especially for prevention of recurrence of the transient cerebral ischemic attack, and prevention/treatment of deep vein thrombosis or DIC.
  • the agents of the present invention are used as a drug for these diseases, preventive administration is recommended and such use is particularly important since the agents of the present invention are neither a direct thrombolytic agent nor a direct anti-platelet agents.
  • the agents of the present invention are adapted for preventive use in patients suffering from thrombophilia or patients having the risk factor of thrombus/embolism for the purpose of preventing thrombus/embolism.
  • thrombosis is easily generated at the site of the lesion or the transplantation, and such thrombosis often triggers cerebral infarction, which is more than often a fatal attack.
  • the agents of the present invention have a good potential to be a potent drug for preventing onset of the thrombus/embolism, and in particular, cerebral embolism induced in such patients.
  • the agents of the present invention can be administered by oral administration with less side effects such as bleeding, and therefore, the agents of the present invention can be reliably used for a long time with no need of frequent monitoring.
  • the agents of the present invention are preventives and/or therapeutics for embolism associated with atrial fibrillation/artificial valve or valvular heart disease.
  • the agents of the present invention are preferably preventives of the onset of cerebral embolism associated with such disease.
  • the agents of the present invention are also preventives and/or therapeutics, and in particular, a preventives of the onset of transient cerebral ischemic attack; and a preventives and/or therapeutics for deep vein thrombosis or DIC.
  • compositions containing the compounds of the present invention as an active ingredient are also effective as veterinary drugs and have high value of use.
  • the compositions are also useful as a reagent adapted for use in measuring various blood coagulative functions and as a laboratory reagents.
  • compositions are also useful as preventives/therapeutics for infection by influenza virus based on the inhibitory activity for the propagation of the influenza virus, and also, as preventives/therapeutics for periodontal disease.
  • FXa inhibitory activity is measured in accordance with the method of Kettner et al. (Journal of Biological Chemistry, vol. 265, pages 18289 to 18297, 1990).
  • human FXa product of Enzyme Research Laboratories, Inc., 0.019 U/ml
  • DMSO dimethylsulfoxide
  • S-2222 Chiromogenix AB, 0.4 mM
  • the mixtures are incubated at 37°C in Tris-hydrochloric acid buffer (pH 7.5) while the absorbance at 405 nm is measured continuously.
  • the initial reaction velocity is compared with the value for a control containing no test compound. It should be noted that the FXa inhibitory activity of the test compound is generally indicated as IC 50 .
  • the strength is in the range of 0.1 nM to 1 ⁇ M in terms of IC 50 .
  • Table 1 shows typical measurements. Test compound (compounds of the Examples) IC 50 ( ⁇ M) Example 1 0.0032 Example 5 0.0029 Example 10 0.0054 Example 25 0.0015 Example 50 0.0019 Example 59 0.0034 Example 61 0.0028
  • Activated partial thromboplastin time is measured in the presence of the test compounds diluted at various concentrations.
  • a test compound diluted with DMSO at various concentrations is mixed with human plasma and APTT reagent. The mixture is incubated at 37°C for 2 minutes; calcium chloride (25 mM) is added to the mixture; and the coagulation time is thereafter measured.
  • the anticoagulant activity of the test compound is described in terms of the concentration required to double the coagulation time for the case where no test compound is added.
  • the compounds of the present invention were found to be effective in extending the APTT.
  • the effects of the compounds of the present invention are shown in Table 2.
  • Test compound Compounds of the Examples
  • Male Wistar rats (200 g - 300 g; Japan SLC Inc.) that have been starved for more than 12 hours are administered through a femoral vein with a single dose of a drug (3 - 30 mg/kg) dissolved in physiological saline (or 10% DMSO solution), and the blood is collected at a certain time interval (3.8% sodium citrate, 1/10 volume), and plasma is then separated by centrifugation at 3000 rpm for 10 minutes.
  • Prothrombin time PT is measured by the procedure as described below by using the separated plasma.
  • the intravenously administered compounds of the present invention were found to be effective in extending the PT on account of enzyme inhibition.
  • test compound is compulsorily administered by oral administration using an oral introducer instead of the administration from the femoral vein at a single dose in the test a), and a certain volume of the blood is collected at a certain time interval at 3.8% sodium citrate, 1/10 volume.
  • the blood is evaluated by the procedure as described in a) for extrinsic coagulation time and intrinsic coagulation time.
  • the compounds of the present invention were found to be effective in extending the coagulation time upon oral administration of 10 - 100 mg.
  • compositions of the present invention may contain at least one compound represented by formula (I) (as already defined above) or salts thereof as an active ingredient. They may also contain any pharmaceutical acceptable carriers.
  • formula (I) as already defined above
  • salts thereof as an active ingredient. They may also contain any pharmaceutical acceptable carriers.
  • the preferred examples of the compounds of the general formula (I) have already been mentioned.
  • the compounds of the present invention exhibit potent inhibitory action for FXa activity without exhibiting any inhibitory activity for trypsin, chymotrypsin, or thrombin, and the specificity of the compounds is high. Furthermore, the compounds of the present invention exhibit antithrombotic action when orally administered at a dose of 0.1 to 10 mg/kg, or intravenously administered at a dose of 0.01 to 1 mg/kg in rats.
  • the compounds of the present invention does not exhibit prolongation of bleeding time when orally administered at a dose of 10 mg/kg or intravenously administered at a dose of 1 mg/kg in rats. Accordingly, the compounds of the present invention exhibit the anticoagulation action with no risk of showing bleeding tendency, and this is a significant difference from heparin and warfarin, which are known anticoagulants. In addition, the compounds of the present invention exhibit excellent oral absorption, adequate long-lasting action, as well as high safety.
  • the compounds of the present invention may be administered to the disease as described above which is to be prevented and treated by the present invention either alone or in combined application with other pharmacologically active component.
  • pharmacologically active components include known fibrinolytics (for example, tissue plasminogen activators (tPA) and their derivatives (including modified agents or the so called “second generation” agents), urokinase, and streptokinase); known anticoagulants (for example, warfarin, heparin, and thrombomodulin); known inhibitors of platelet aggregation (for example, aspirin, thromboxane antagonist, inhibitor of thromboxane synthesis, and GPIIb/IIIa antagonist); known therapeutic agents for hyperlipidemia (for example, clofibrate and related drugs, HMG-CoA reductase inhibitor, and EPA-E); and known hypotensive agents (for example, nifedipine and diltiazem).
  • fibrinolytics for example
  • combined application covers not only the administration of a combination drug containing both the compound of the present invention and another pharmacologically active ingredient but also the case where the two are in separate dosage forms and administered either at a time or at different times.
  • the mode of administration is in no way limited as long as the compound of the present invention and another pharmacologically active ingredient exist simultaneously in the patient's blood.
  • the pharmaceutical composition containing one or more compounds of the present invention or its pharmaceutically acceptable salt as its effective component may be prepared into capsules, pills, tablets, granules, subtle granules, or powder; or alternatively, oral solution such as suspension, emulsion, limonades, elixir, or syrup; injectable solution; transnasal formation; suppository; ointment; epithem; and the like which are orally or perorally administered to human and other animals by using the commonly used pharmaceutical vehicle, excipient, or other additives.
  • Clinical dose of the compound of the present invention to human may be adequately determined in consideration of symptom, body weight, age, sex, and the like of the patient to which the compound is administered.
  • the adult daily dose in oral administration is generally in the range of 0.1 mg to 1000 mg, and preferably 1 mg to 300 mg, and the dose in peroral administration is 0.01 to 300 mg, and preferably 0.1 mg to 100 mg.
  • Such dose may be administered as a single dose or divided into several doses. The dose may vary depending on various conditions, and the dose below the above described range may be sufficient in some cases.
  • capsules, pills, tablets, powder, granules, and the like may be employed for the solid composition.
  • Such solid composition is produced by combining at least one active substance with at least one inactive carrier.
  • the composition may contain an excipient (for example, lactose, saccharose, mannitol, glucose, hydroxy propylcellulose, microcrystalline cellulose, or metasilicic acid), a binder (for example, crystalline cellulose, saccharide, dextrin, hydroxy propylcellulose, hydroxy propylmethylcellulose, polyvinyl pyrrolidone, or Macrogol), a lubricant (for example, magnesium stearate, calcium stearate, or talc), a disintegrant (for example, corn starch, carboxy methyl cellulose, or calcium cellulose glycorate), a stabilizer (for example, lactose and other sugar alcohols or sugar), a solubilizer or a solubilizing aid (for example
  • an excipient for example, lactos
  • the tablet, the pill and the granules may be coated with sugar, gelatin, hydroxy propylmethylcellulosse phthalate or other gastric or enteric film coating.
  • Exemplary injectable solution used for parenteral administration include aseptic aqueous or nonaqueous solution, suspension, and emulsion.
  • Exemplary carriers for the aqueous solution and suspension include water for injection and physiological saline, and exemplary carriers for the nonaqueous solution and suspension include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and alcohols such as ethylalcohol, and polysorbate 80 (TM).
  • composition may further comprise an isotonic agent, antiseptic, emolient, emulsifier, dispersant, stabilizer, solubilizer, solubilizing aid, or other additives as described above, and these additives may be sterilized, for example, by filtration with a membrane filter, inclusion of an antimicrobial agent, or UV irradiation.
  • an isotonic agent for example, antiseptic, emolient, emulsifier, dispersant, stabilizer, solubilizer, solubilizing aid, or other additives as described above, and these additives may be sterilized, for example, by filtration with a membrane filter, inclusion of an antimicrobial agent, or UV irradiation.
  • composition may be also produced in the form of sterilized solid composition which can be dissolved, emulsified, or suspended before its use for use as an injectable solution.
  • the compound of the present invention has low solubility, the compound may be solubilized as desired.
  • solubilization may be accomplished by any of the processes known in the art to be applicable for the production of drugs, for example, addition of a surfactant (a polyoxyethylene hydrogenated castor oil, a polyoxyethylene sorbitan higher fatty acid ester, a sugar fatty acid ester, and the like); and formation of a solid dispersion of the drug and a solubilizer, for example, a polymer (a water-soluble polymer such as polyethylene glycol (PEG), hydroxy propyl methylcellulose (HPMC), or polyvinyl pyrrolidone (PVP); or an enteric polymer such as hydroxy propyl methylcellulose phthalate (HPMCP), or methyl methacrylate-methacrylic acid copolymer (Eudragid L,S (TM) manufactured by Rohm and Haas Company)).
  • a surfactant a polyoxyethylene hydrogenated castor oil, a polyoxyethylene sorbitan higher fatty acid ester, a sugar fatty acid ester,
  • an inclusion compound may be formed by using ⁇ -, ⁇ -, or ⁇ -cyclodextrin, hydroxy propyl cyclodextrin, or the like.
  • the procedure employed for the solubilization may also be modified as desired depending on the drug desired by referring to Nagai, T., et al., "Monograph in Pharmacology No.1, Biochemical Availability", Soft-Science Inc., 78-82(1988) or Utsumi, I., et al., “Current Pharmaceutical Technology and Its Application", Iyaku Journal, 157-159(1983).
  • the preferred is formation of a solid dispersion comprising the drug and the solubilizer which exhibits an improved solubility (JP-A 56-49314, FR2460667).
  • Compound M is the compound of the present invention represented by formula (I) or its pharmaceutically acceptable salt, and to be more specific, a compound selected from the compounds described in Examples.
  • Injectable solution 1.0 mg/ml
  • Compound M 1.0% W/V Sodium phosphate buffer 3.6% W/V 1M
  • Nuclear magnetic resonance (NMR) spectrum was measured by using JEOL JNM-EX270 FT-NMR (manufactured by JEOL Ltd.) or JEOL JNM-LA300 FT-NMR (indicated by * in the data; manufactured by JEOL Ltd.).
  • Infrared absorption spectrum (IR) was measured by using HORIBA FT-200 FT-IR (indicated by * in the data; manufactured by HORIBA Ltd.) or HORIBA FT-720 FT-IR (manufactured by HORIBA Ltd.).
  • HRMS high resolution mass spectrometry
  • HRMS High resolution mass spectrometry
  • Glycine ethyl ester hydrochloride (9.88 g) was suspended in methylene chloride (500 ml), and triethylamine (20.2 ml) and then 6-chloronaphthalene-2-sulfonyl chloride (17.6 g) were added to the suspension under cooling with ice. After stirring at room temperature for 1 hour and adjusting the mixture to pH 2 by addition of 1N hydrochloric acid, the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated sodium chloride solution and dried over anhydrous. sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Step A-1 To a solution of the compound obtained in Step A-1 (2.50 g) in N,N-dimethylformamide (25 ml) were added potassium carbonate (1.58 g) and sodium iodide (1.14 g), and a solution of 1-acetoxy-3-chloroacetone (1.72 g) in N,N-dimethylformamide (7 ml) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, and the mixture was extracted with diethyl ether after adding water. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Step A-2 To a solution of the compound obtained in Step A-2 (1.6 g) and 4-(aminomethyl)-1-benzyl-4-hydroxypiperidine (800 mg) in toluene (200 ml) was added p-toluenesulfonic acid monohydrate (34.0 mg), and the mixture was heated under reflux for 1 hour by using a Dean Stark. The reaction mixture was allowed to cool, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate) to obtain the title compound (1.08 g).
  • Step A-3 To a solution of the compound obtained in Step A-3 (425 mg) in methanol (11 ml) was added 1N aqueous solution of sodium hydroxide (2.8 ml) under cooling with ice. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The residue was washed by adding water, collected by filtration, and dried under reduced pressure to obtain the title compound (365 mg).
  • Step A-4 To a solution of the compound obtained in Step A-4 (100 mg), benzyltriethylammonium chloride (4.0 mg), and dimethyl sulfate (0.018 ml) in methylene chloride (2 ml) was gradually added 50% aqueous solution of sodium hydroxide (0.6 ml) with vigorous stirring under cooling with ice. After stirring the reaction mixture at room temperature for 2 hours, water was added under cooling with ice, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • racemic body of the title compound (50.9 mg) was mixed with (+)-O,O'-dibenzoyl-D-tartaric acid (32.7 mg), and methanol (6.6 ml) was added to the mixture. After stirring the mixture, the insoluble content was collected by filtration and dried in vacuum. The thus obtained crystals (20 mg) were desalted by using saturated aqueous solution of sodium hydrogencarbonate to obtain the (+) form of the title compound at an optical purity of 94.6%ee. The (-) form of the title compound was also obtained by the similar manner using (-)-O,O'-dibenzoyl-L-tartaric acid.
  • the resulting residue was dissolved in a mixed solution of methanol (1.33 l) and methylene chloride (1.33 l), and 1N aqueous solution of sodium hydroxide (140 ml) was added dropwise to this solution under cooling with ice. After stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure. To the residue was added saturated aqueous solution of ammonium chloride, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Step B-2 To a solution of the compound obtained in Step B-2 (76.5 g) in acetonitrile (1.53 1) was added trimethylsilyl iodide (32 ml) under cooling with ice. After stirring the mixture for 45 minutes under cooling with ice, the reaction mixture was poured into 1N hydrochloric acid under cooling with ice, and n-hexane was added to this mixture. The mixture was stirred for separation, and the aqueous layer was washed with n-hexane followed by addition of methylene chloride. 2N aqueous solution of sodium hydroxide was added with stirring under cooling with ice and the mixture was adjusted to pH 11.
  • Step C-1 The procedure of Step C-1 was repeated by using the compound obtained in Step D-3 (100 mg) to obtain the title compound (145 mg).
  • Step C-2 was repeated by using the compound obtained in Step D-4 (72.5 mg) to obtain the title compound (67.0 mg).
  • Example 1 ⁇ Step A-4> was repeated by using the compound obtained in Example 7 ⁇ Step B-1> (938 mg) to obtain the title compound (626 mg).
  • Example 1 ⁇ Step A-6> was repeated by using the compound obtained in Example 1 ⁇ Step A-3> (584 mg) to obtain the title compound (430 mg).
  • Step A-1 The compound obtained in Step A-1 (370 mg) was used to synthesize according to the procedure of Example 1 ⁇ Step A-7> to thereby obtain the title compound (30.0 mg).
  • Step A-1 The compound obtained in Step A-1 (300 mg) was used to synthesize according to the procedure of Example 1 ⁇ Step A-6> to thereby obtain the title compound (276 mg).
  • Example 3 ⁇ Step A-2> 300 mg was used to synthesize according to the procedure of Example 4 ⁇ Step A-1> to thereby obtain the title compound (168 mg).
  • Step B-1 The compound obtained in Step B-1 (48 mg) was dissolved in formic acid (1.0 ml) and the solution was stirred overnight at room temperature. The mixture was solidified by addition of diethyl ether and the supernatant was removed by decantation and dried in vacuum to obtain the title compound (35.3 mg).
  • Step A-2 The compound obtained in Step A-2 (175 mg) was dissolved in 10% hydrogen chloride-methanol solution (2 ml) and the solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was solidified by addition of diethyl ether, and thereafter fully triturated. The solvent was distilled off under reduced pressure to obtain the title compound (160 mg).
  • the reaction mixture was concentrated and to the resulting residue was added 1N aqueous solution of sodium hydroxide.
  • the mixture was extracted with methylene chloride.
  • the organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain the title compound (3.47 g).
  • Example 1 ⁇ Step A-7> was repeated by using the compound obtained in Step B-1 (2.60 g) to obtain the title compound (240 mg).
  • Step 1 To a solution of the compound obtained in Step 1 (76.6 mg) in methanol (2 ml) was added 1N aqueous solution of sodium hydroxide (2.84 ml) at room temperature. The reaction mixture was stirred at room temperature for 20 minutes and the solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with methylene chloride. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (63.1 mg).
  • Example 2 ⁇ Step 1> was repeated by using the compound obtained in Example 9 ⁇ Step 5> to obtain the title compound (293 mg).
  • Example 9 The compound obtained in Example 9 ⁇ Step 1> (2.46 g) was suspended in methylene chloride (90 ml) and to the suspension were added triethylamine (1.56 ml) and then (E)-4-chlorostyrylsulfonyl chloride (2.26 g) under cooling with ice. The mixture was stirred at room temperature for 4 hours and water was added thereto. The mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and thereafter the solvent was distilled off under reduced pressure.
  • Example 2 To a solution of the compound obtained in Example 1 (111 mg) in methanol (0.4 ml) was added methanesulfonic acid (0.01313.6 ml) and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was crystallized by addition of diethyl ether. The supernatant was removed by decantation and the solvent was distilled off under reduced pressure to obtain the title compound (119 mg).
  • Example 12 The procedure of Example 12 was repeated by using the (-)-1,4-diaza-4-(6-chloronaphthalen-2-ylsulfonyl)-6-(methoxymethyl)-7-oxa-1'-(4-pyridyl)spiro[bicyclo[4.3.0]nonane-8,4'-piperidin]-2-one (111 mg) produced by the optical resolution method described in Example 1 ⁇ Step A-7> to obtain the title compound (119 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 3 ⁇ Step A-2> (33.0 mg) to obtain the title compound (38.0 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 4 ⁇ Step A-3> (40.0 mg) to obtain the title compound (43.0 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 7 ⁇ Step A-4> (33.0 mg) to obtain the title compound (34.2 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 9 ⁇ Step 6> (27.8 mg) to obtain the title compound (30.0 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 10 ⁇ Step 2> (31.2 mg) to obtain the title compound (34.0 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 11 ⁇ Step 5> (30.6 mg) to obtain the title compound (31.5 mg).
  • Example 4 ⁇ Step A-1> was repeated by using the compound obtained in Example 1 ⁇ Step B-1> (4.00 g) to obtain the title compound (3.90 g).
  • Step 1 The compound obtained in Step 1 (100 mg) was dissolved in a mixed solution of tetrahydrofuran (1 ml) and ethanol (1 ml) and to the solution were added lithium chloride (18.6 mg) and sodium borohydride (16.5 mg). After stirring at room temperature for 3 hours, saturated aqueous solution of ammonium chloride was added to the reaction mixture under cooling with ice, followed by extraction with methylene chloride. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 20 ⁇ Step 5> (50.0 mg) to obtain the title compound (59.3 mg).
  • Example 20 ⁇ Step 2> was repeated by using the compound obtained in Example 4 ⁇ Step A-3> (50.0 mg) to obtain the title compound (39.2 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 25 ⁇ Step 4> (56.0 mg) to obtain the title compound (58.9 mg).
  • Example 28 The procedure of Example 28 was repeated by using the compound obtained in Example 27 (20 mg) and using isopropyl alcohol (0.028 ml) instead of methanol to obtain the title compound (18.1 mg).
  • HRMS:C 29 H 31 ClN 4 O 6 S(M + ) Calculated: 598.1652, Found: 598.1668
  • Example 28 The procedure of Example 28 was repeated by using the compound obtained in Example 27 (20 mg) and using n-propyl alcohol (0.026 ml) instead of methanol to obtain the title compound (15.3 mg).
  • Example 28 The procedure of Example 28 was repeated by using the compound obtained in Example 27 (20 mg) and using allyl alcohol (0.025 ml) instead of methanol to obtain the title compound.
  • IR(KBr)cm -1 1747, 1678, 1597, 1350, 1167, 972
  • Example 28 The procedure of Example 28 was repeated by using the compound obtained in Example 27 (20 mg) and using 2-methoxyethanol (0.028 ml) instead of methanol to obtain the title compound (13.1 mg).
  • Dioxane (1.0 ml) solidified in a bath cooled to -20 °C was added concentrated sulfuric acid (0.1 ml). The mixture was warmed to room temperature to obtain a homogenous solution. The solution was solidified again in the bath cooled to -20 °C and the compound obtained in Example 27 (18.0 mg) was added. The mixture was warmed to room temperature to obtain a homogenous solution, which was solidified in the bath cooled to -20 °C. After adding liquid isobutylene (0.7 ml), the mixture was stirred in a sealed tube at room temperature for 5 hours. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with methylene chloride.
  • Example 12 The procedure of Example 12 was repeated by using the (-) form of the compound obtained in Example 35 (100 mg) to obtain the title compound (104 mg).
  • Example 27 The procedure of Example 27 was repeated by using the compound obtained in Example 35 (1.80 g) to obtain the title compound (1.63 g).
  • IR(KBr)cm -1 1664, 1647, 1543, 1460, 1350, 1169
  • Example 28 The procedure of Example 28 was repeated by using the compound obtained in Example 37 (160 mg) to obtain the title compound (153 mg).
  • IR(KBr)cm -1 1749, 1678, 1599, 1349
  • Example 28 The procedure of Example 28 was repeated by using the compound obtained in Example 37 (150 mg) and using isopropyl alcohol (0.206 ml) instead of methanol to obtain the title compound (147.7 mg).
  • HRMS:C 29 H 31 ClN 4 O 6 S (M + ) Calculated: 598.1652, Found: 598.1667
  • Example 28 The procedure of Example 28 was repeated by using the compound obtained in Example 37 (170 mg) and using n-propyl alcohol (0.023 ml) instead of methanol to obtain the title compound (158 mg).
  • Example 28 The procedure of Example 28 was repeated by using the compound obtained in Example 37 (160 mg) and using allyl alcohol (0.196 ml) instead of methanol to obtain the title compound (158 mg).
  • IR(KBr)cm -1 1747, 1678, 1597, 1419, 1352
  • Example 28 The procedure of Example 28 was repeated by using the compound obtained in Example 37 (180 mg) and using 2-methoxyethanol (0.255 ml) instead of methanol to obtain the title compound (178.6 mg).
  • HRMS:C 29 H 31 ClN 4 O 7 S(M + ) Calculated: 614.1602, Found: 614.1572
  • Example 33 The procedure of Example 33 was repeated by using the compound obtained in Example 37 (160 mg) to obtain the title compound (146 mg).
  • IR(KBr)cm -1 1738, 1678, 1597, 1352, 1157, 1132
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 38 (110 mg) to obtain the title compound (12 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 39 (110 mg) to obtain the title compound (125 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 40 (110 mg) to obtain the title compound (126 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 41 (110 mg) to obtain the title compound (129 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 42 (110 mg) to obtain the title compound (127 mg).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 43 (119 mg) to obtain the title compound (137 mg).
  • Example 50 The procedure of Example 50 was repeated by using the (+) form of the compound obtained in Example 35 (40.0 mg) to obtain the (+) form of the title compound (20.5 mg).
  • IR(KBr)cm -1 1626, 1603, 1398, 1348, 1169
  • Example 50 was repeated by using the (-) form of the compound obtained in Example 35 (55.0 mg) to obtain the (-) form of the title compound (28.3 mg).
  • IR(KBr)cm -1 1657, 1626, 1603, 1396, 1348, 1169
  • Example 23 The procedure of Example 23 was repeated by using the (-) form of the compound obtained in Example 35 and using ethyl p-toluenesulfonate instead of methyl p-toluenesulfonate to obtain the title compound.
  • IR(KBr)cm -1 3064, 1676, 1649, 1349, 1221, 1192, 1169, 1124, 1012
  • Example 36 and 52 can be repeated by using the (+) form obtained in Example 35 to thereby obtain the respective (+) bodies. Further, the procedures of Examples 37 and 38 - 49 can be repeated to obtain the respective (+) bodies.
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 56 (40.0 mg) to obtain the title compound (43.7 mg).
  • the organic layer was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate.
  • the amorphous content (450 mg) obtained by distilling off the solvent under reduced pressure was dissolved in methylene chloride (1.3 ml) and to the solution were added glycine ethyl ester hydrochloride (50.4 mg) and acetic acid (0.03 ml). Thereafter, sodium triacetoxy borohydride (127 mg) was added under cooling with ice and the mixture was stirred at room temperature for 8 hours. After adding saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture and extracting with methylene chloride, the organic layer was wished with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate.
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 61 ⁇ Step 2> (50.9 mg) to obtain the title compound (50.8 mg).
  • Example 2 ⁇ Step 1> was repeated by using the compound obtained in Example 7 ⁇ Step B-1> (930 mg) to obtain the title compound (480 mg).
  • Example 2 ⁇ Step 2> was repeated by using the compound obtained in ⁇ Step 1> (300 mg) to obtain the title compound (197 mg).
  • Example 2 The procedure of Example 2 ⁇ Step 1> was repeated by using the compound obtained in Example 25 ⁇ Step 3> (390 mg) to obtain the title compound (363 mg).
  • Example 27 The procedure of Example 27 was repeated by using the compound obtained in Example 67 ⁇ Step 2> (10 mg) to obtain the title compound (1.9 mg).
  • Example 1 ⁇ Step A-2> was repeated by using the compound obtained in Example 1 ⁇ Step A-1> (1.0 g) and using chloroacetone (0.368 ml) instead of 1-acetoxy-3-chloroacetone to obtain the title compound (1.08 g).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 69 ⁇ Step 4> (35.0 mg) to obtain the title compound (37.9 mg).
  • Example 1 ⁇ Step C-1> was repeated by using the compound obtained in Step 1 (5.56 g).
  • the thus obtained compound was used as the starting material to synthesize according to the procedure of Example 1 ⁇ Step C-2> to thereby obtain the title compound (1.50 g).
  • Example 7 was repeated by using the compound obtained in Step 2 (0.53 g) to obtain the title compound (0.30 g).
  • Example 50 The procedure of Example 50 was repeated by using the compound obtained in Example 71 ⁇ Step 4> (90 mg) to obtain the title compound (70 mg).
  • IR(KBr)cm -1 3445, 2949, 1666, 1599, 1348, 1167
  • Example 1 ⁇ Step A-3> was repeated by using the compound obtained in Example 1 ⁇ Step A-2> (10.3 g) and 9-amino-4-(aminomethyl)-1-benzylpiperidine (5.26 g) to obtain the title compound (7.76 g).
  • Example 20 ⁇ Step 5> was repeated by using the compound obtained in Step 2 (3.30 g) to obtain the title compound (2.50 g).
  • IR(KBr)cm -1 :3336, 2939, 1657, 1601, 1454, 1421, 1346, 1167
  • Example 1 ⁇ Step A-5> was repeated by using the compound obtained in Example 7466 (0.34 g) to obtain the title compound (0.14 g).
  • IR(KBr)cm -1 was repeated by using the compound obtained in Example 7466 (0.34 g) to obtain the title compound (0.14 g).
  • Example 12 The procedure of Example 12 was repeated by using the compound obtained in Example 75 (0.13 g) to obtain the title compound (0.17 g).
  • Example 1 ⁇ Step A-5> was repeated by using the compound obtained in Example 73 ⁇ Step 3> (1.50 g) to obtain the title compound (0.75 g).
  • IR(KBr)cm -1 was used for the procedure of Example 1 ⁇ Step A-5> to obtain the title compound (0.75 g).
  • Example 1 ⁇ Step A-4> was repeated by using the compound obtained in Example 73 ⁇ Step 1> (2.00 g) to obtain the title compound (1.75 g).
  • the aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with methylene chloride.
  • the organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography [ChromatorexNHTM](eluent; methylene chloride - 2% methanol/methylene chloride) to obtain the title compound (0.15 g).
  • Example 79 The procedure of Example 79 was repeated by using the compound obtained in Example 75 (130 mg) to obtain the title compound (69.0 mg).
  • Example 79 The procedure of Example 79 was repeated by using (+)-1,4-diaza-4-(6-chloronaphthalen-2-ylsulfonyl)-6-(methoxymethyl)-7-oxa-1'-(4-pyridyl)spiro[bicyclo[4.3.0]nonane-8,4'-piperidin]-2-one (100 mg) to obtain the title compound (90.7 mg).
  • Example 79 The procedure of Example 79 was repeated by using (-)-1,4-diaza-4-(6-chloronaphthalen-2-ylsulfonyl)-6-(methoxymethyl)-7-oxa-1'-(4-pyridyl)spiro[bicyclo[4.3.0]nonane-8,4'-piperidin]-2-one (100 mg) to obtain the title compound (84.1 mg).
  • the diethyl ether layer was further extracted with 1N hydrochloric acid and combined with the above aqueous layer.
  • the aqueous layer was adjusted to pH 9 with sodium carbonate under cooling with ice and extracted with methylene chloride.
  • the organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.
  • Step 7 To a solution of the compound obtained in Step 7 (4.5 mg) in methanol (1 ml) was added 10% palladium-active carbon (2 mg) and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite and washed with methanol. The filtrate was concentrated to obtain the title compound quantitatively.
  • Example 1 ⁇ Step A-1> was repeated by using the compound obtained in Step 1 (10 mg) to obtain the title compound (22 mg).
  • FIGs. 1 - 9 The structures of the compounds of the present invention obtained in Examples mentioned above are shown in FIGs. 1 - 9.
  • the synthesis routes of the compounds of the present invention are shown in FIGs. 11 - 20.
  • a purified sample of human FXa was purchased from Enzyme Research Laboratories, Inc. and the sample was digested with a protease in accordance with J. Biol. Chem., 271, 16614-16620(1996) to remove Gla domain (1-44 (chymotrypsin No.)).
  • the Des-Gla-FXa was purified by using Mono-P (Amersham Pharmacia Biotech Inc.), and the crystallization was accomplished by hanging drop vapor diffusion method.
  • the complex crystal was subjected to X-ray diffraction experiment at a low temperature of -180°C using diffractometer R-AXIS (Rigaku K.K.) and data set was collected at 2.8 ⁇ resolution.
  • This crystal contained 1 molecule in the asymmetric unit, and the Vm value was 2.2 ⁇ 3 /Dalton.
  • the structure was analyzed by molecule replacement method using REPLACE (Tong, 1993) included in crystallographic packaging program Xsight (MSI Inc.). 1hcg of protein data bank was used for the initial structure model.
  • Crystallographic structure of these atom coordinates was refined by using X-PLOR (Brunger, 1987). The refinement was conducted by repeating the calculation by X-PLOR and adjustment of the atom position by manual adjustment to thereby minimize R factor, and this refinement was continued until the value of approximately 20% was obtained.
  • column 1 record ID of the PDB file
  • column 2 serial number of coordinate in the PDB file
  • column 3 atom name
  • column 4 name of the amino acid residue
  • column 5 amino acid residue No. (chymotrypsin No.)
  • column 6 X coordinate of the atom
  • column 7 Y coordinate of the atom
  • column 8 Z coordinate of the atom
  • column 9 filling factor (fixed to 1.0)
  • column 10 temperature factor.
  • Hydrogen atoms in the coordinate data are those generated in the course of calculation on program X-PLOR, and the data do not indicate accurate position of the hydrogen atoms.
  • FIG. 37 shows the structure of the FXa (ribbon diagram)
  • FIG. 38 shows the crystal structure of the FXa - Compound A complex (ribbon diagram).
  • FIGS. 37 and 38 were prepared by using the program MOLSCRIPT (Kraulis, P., J. Appl. Crystallogr., 24, 946-950(1991)).
  • FIG. 39 shows active sites of the human FXa.
  • FIG. 40 shows active sites of the human FXa - Compound A complex.
  • FIG. 41 shows the stereo view of the active sites of the human FXa - Compound A complex.
  • FIG. 41 was prepared by using the program MOLSCRIPT.
  • the naphthalene ring moiety of the Compound A is bonded to S1 pocket of the FXa by hydrophobic interaction; the chlorine atom added to the naphthalene has undergone interaction with the benzene ring moiety of the Tyr228 side chain in the S1 pocket; the Compound A has not undergone electrostatic interaction with the Asp189 of the FXa in the S1 pocket; and the binding mode of the Compound A to the S1 pocket is totally different from the binding mode of DX-9065a and FX-2212a which are known FXa inhibitors whose structure of the complex has been found out.
  • 4-aminopyridine moiety of the Compound A binds to the S3 pocket by the interaction between the basic moiety of the 4-aminopyridine moiety and the electrically negative condition of the S3 pocket, and such situation is believed to contribute for the selectivity of the Compound A for trypsin, thrombin, protein C and tissue plasminogen activator.
  • hydrogen bond is formed between the carbonyl oxygen atom of the Compound A and the NH group of the Gly218 backbone.
  • the structural activity correlation of the compound of the present invention is believed to indicate that this bond is not necessary for the inhibition of the FXa, but has secondary effects such as increase of the FXa inhibitory activity.
  • Conformation of the Compounds B and C other than the halogenonaphthalene moiety was searched by using Search Compare with the halogenonaphthalene moiety of the Compounds B and C fixed in the S1 pocket.
  • the conformation was generated by systematically rotating the bonds in the Compound B or C which were estimated to be rotatable.
  • the rotation angle of the bond was 60 degrees to 300 degrees at an increment of 120 degrees in dihedral angle in the case of the bond between Sp3 atoms; and 0 degree to 330 degrees at an increment of 30 degrees in dihedral angle in the case of the bond between Sp3 atom and Sp2 atom. These rotation angles are the angles that had been recommended by MSI Inc. as the search conditions for generating stable conformation of the compound.
  • the pharmacophore illustrating the present invention has been derived on the basis of the novel tricyclic compound having spiro union. This compound has played an important role in finding the novel pharmacophore which has never been reported for FXa since the three-dimensional arrangement of the three rings is fixed in this compound. Unexpectedly, it has also been confirmed that.the thus derived pharmacophore is quite important and fully applicable by molecular designing means to a compound which does not have such skeleton, and in particular, to a compound having a flexible three-dimensional arrangement.
  • the compound of the present invention specifically inhibits FXa, and exhibits strong anticoagulation action.
  • the compound of the present invention is also easy to use since it exhibits high oral absorbability as well as long-lasting action and high safety. Accordingly, the compound of the present invention is very useful as an anticoagulant.
  • the pharmacophore illustrating the present invention derived from the compound of the present invention is capable of providing information useful in identifying or designing the inhibitors which competitively bind to the active site of the FXa or its fragment.

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Claims (15)

  1. Composé représenté par la formule (I), ou son sel acceptable du point de vue pharmaceutique :
    Figure 03300001
    dans laquelle A est un atome d'hydrogène, ou
    un groupe choisi parmi (1) un groupe hydrocarboné cyclique pentagonal ou hexagonal saturé ou insaturé, ou un groupe hétérocyclique pentagonal ou hexagonal saturé ou insaturé, (2) un groupe amino, et (3) un groupe imidoyle (les groupes (1) à (3) étant facultativement substitués) ;
    B est une simple liaison, un groupe carbonyle, -S(O)x-, ou un groupe alkylène en C1-2 facultativement substitué ;
    D est un atome d'hydrogène, -CO-R5 (où R5 est un atome d'hydrogène ou un substituant), ou un groupe alkyle en C1-6 facultativement substitué ;
    X est un atome d'azote ou un groupe méthlne facultativement substitué par un groupe A'-B'- (où A' représente un groupe choisi parmi les groupes définis pour A et B' représente un groupe choisi parmi les groupes définis pour B) ;
    Y est un atome d'oxygène, -S(O)y-, ou un groupe Imino (-NH-) facultativement substitué ;
    Z est un groupe méthylène, un groupe carbonyle, ou un groupe thiocarbonyle ;
    T est -S(O)z-, un groupe carbonyle, ou un groupe alkylène en C1-2 facultativement substitué ;
    Q est un groupe hydrocarboné ou un groupe hétérocydique, qui est facultativement substitué ;
    l, m, n, x, y et z représentent indépendamment un nombre entier choisi parmi 0, 1 et 2, à la condition que I et m ne soient pas simultanément 0 ; et r est le nombre entier 0 ou 1 et les trois cycles (le cycle contenant X, le cycle contenant Y et le cycle contenant Z) sont indépendamment et facultativement substitués ; et la liaison indiquée par le trait pointillé et le trait plein dans le cycle contenant Z est une simple liaison ou une double liaison (lorsque r est 0).
  2. Au moins un composé choisl parmi les composés tels que décrits ci-dessous, ou son Isomère optique (+) ou (-), ou son sel acceptable du point de vue pharmaceutique :
    1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(méthoxy-méthyl)-7-oxa-1'-(4-pyrldyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    (-)-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(méthoxy-méthyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(hydroxy-méthyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(éthoxy-carbonylmétoxyméthyl)-7-oxa-1'-(4-pyridyl)-spiro-[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    6-(acétoxyméthyl)-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxa-1'-(4-pyrimidinyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-((E)-4-chlorostyrylsulfonyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(2-méthoxy-éthoxyméthyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3,0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(éthoxy-carbonyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one méthane-sulfone ;
    (-)-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(éthoxy-carbonyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    (-)-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(méthoxy-carbonyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    (-)-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(iso-propoxycarbonyl)-7-oxa-1'-(4-pyridyl)spiro[bicyclo[4.3.0]-nonane-8,4'-pipéridin]-2-one ;
    (-)-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxa-6-(propoxycarbonyl)-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    (-)-6-(allyloxycarbonyl)-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxa-1'-(4-pyridyl)-spiro-[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    (-)-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(2-méthoxy-éthoxycarbonyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]-nonane-8,4'-pipéridin]-2-one ;
    (-)-1,4-diaza-6-(t-butoxycarbonyl)-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxa-2-oxo-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridine]-6-carboxylate d'ammonium ;
    (+)-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxa-2-oxo-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridine]-6-carboxylate d'ammonium;
    (-)-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxa-2-oxo-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridine]-6-carboxylate d'ammonium ;
    4-[1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(méthoxy-méthyl)-7-oxa-2-oxospiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-1'-yl]-pyridine 1-oxyde ;
    1'-acétimidoyl-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxaspiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    6-(aminométhyl)-1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(éthoxy-carbonylaminométhyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo-[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(morpholino-méthyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-méthyl-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    4-[1,4-diaza-4-(6-chloronaphtalén-2-ylsulfonyl)-7-oxa-2-oxo-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-6-yl]-butylate d'ammonium ;
    1,4,7-triaza-4-(6-chloronaphtalén-2-ylsulfonyl)-6-(méthoxy-méthyl)-7-méthyl-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4,7-triaza-4-(6-chloronaphtalén-2-ylsulfonyl)-(6-méthoxy-méthyl)-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(7-chloro-2H-benzopyran-3-ylsulfonyl)-(6-méthoxy-méthyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(7-chloro-2H-benzopyran-3-ylméthyl)-(6-méthoxy-méthyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chlorobenzothiophén-2-ylsulfonyl)-(6-méthoxy-méthyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(6-chlorobenzothiophén-2-ylméthyl)-(6-méthoxy-méthyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(5-chlorobenzofuran-2-ylsulfonyl)-(6-méthoxy-méthyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ;
    1,4-diaza-4-(5-chlorobenzofuran-2-ylméthyl)-(6-méthoxy-méthyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one ; et
    1,4-diaza-4-(6-chlorobenzofuran-2-ylsulfonyl)-(6-méthoxy-méthyl)-7-oxa-1'-(4-pyridyl)-spiro[bicyclo[4.3.0]nonane-8,4'-pipéridin]-2-one.
  3. Composé selon la revendication 1, ou son sel acceptable du point de vue pharmaceutique, dans lequel Q est :
    1) un groupe alkyle en C1-6 (plus préférablement un groupe alkyle en C1-2) ou un groupe alkényle en C2-6 (plus préférablement un groupe alkyle en C2) substitué par un substituant choisi parmi le substituant (a-1) : un groupe aryle en C6-14, et un substituant (b-1) : un groupe aromatique choisi parmi (i) les groupes hétérocycliques aromatiques monocycliques pentagonaux ou hexagonaux et (II) les groupes hétérocycliques aromatiques fusionnés de huit à douze atomes nucléaires, lesquels contiennent de 1 à 4 hétéroatomes choisis parmi l'atome d'azote, l'atome d'oxygène et l'atome de soufre en plus des atomes de carbone ; ou
    2) un groupe aryle en C6-14 qui est facultativement substitué par 1 à 2 atomes d'halogène ; ou un groupe hétérocyclique qui est (i) un groupe hétérocyclique aromatique monocyclique pentagonal ou hexagonal, (ii) un groupe hétérocyclique aromatique fusionné de huit à douze atomes nucléaires, ou (iii) un groupe hétérocyclique non aromatique, saturé ou Insaturé, de trois à huit atomes nucléaires, lequel contient de 1 à 4 hétéroatomes choisis parmi l'atome d'azote, l'atome d'oxygène et l'atome de soufre en plus des atomes de carbone, dans lequel les atomes de carbone sont facultativement mono- ou di- substitués par un atome d'halogène, et dans lequel le cycle aromatique dans le substituant 1) ci-dessus est facultativement substitué par 1 à 3 substituants choisis parml les atomes d'halogène, les groupes trifluorométhyle, cyano, hydroxyle, amino, nitro, carboxyle, carbamoyle, alkyle en C1-6, alkoxy en C1-6, mono/di-(alkyle en C1-6)amino, di(alkyle en C1-6)carbamoyle, (alkoxy en C1-6)carbonyle, N-(alkyle en C1-6)carbamoyle, N,N-di(alkyle en C1-6)carbamoyle et (alkylénoyle en C2-6)amino,
       et le cycle aromatique dans les substituants 2) est également facultativement mono- ou di-substitué dans une position arbitraire par un substituant choisi parmi les groupes alkyle en C1-6, alkényle en C2-6, alkynyle C2-6, un atome d'halogène, les groupes halo-alkyle en C1-6, cyano, amino, hydroxyle, carbamoyle, alkoxy en C1-6, alkényloxy en C2-6, alkynyloxy en C2-6, alkylthio en C1-6, alkylsulfinyle en C1-6, alkylsulfonyle en C1-6, mono/dl(alkyle en C1-6)amino, (alkoxy en C1-6)carbonyle, alcanoyle en C2-6, alcanoylamino en C2-6, hydroxyalkyle en C1-6, alkoxy en C1-6-alkyle en C1-6, carboxyalkyle en C1-6, (alkoxy en C1-6)carbonyl-alkyle en C1-6, carbamoylalkyle en C1-6, N-(alkyle en C1-6)carbamoyl-alkyle en C1-6, N,N-di-(alkyle en C1-6)carbamoyl-alkyle en C1-6, phényle, phénoxy, phénylthio, phénylsulfinyle, phenylsulfonyle, benzyle et benzoyle, et le cycle aromatique dans ces substltuants peut être substitué par 1 à 3 substituants choisis parmi les atomes d'halogène, les groupes trifluorométhyle, cyano, hydroxyle, amino, nitro, carboxyle, carbamoyle, alkyle en C1-6, alkoxy en C1-6, mono/di-(alkyle en C1-6)amino, di-(alkyle en C1-6)carbamoyle, (alkoxy en C1-6)carbonyle, N-(alkyle en C1-6)carbamoyle, N,N-di-(alkyle en C1-6)carbamoyle et (alkénoyle en C2-8)amino.
  4. Composition pharmaceutique caractérisée en ce que la composition contient un composé représenté par la formule (I), ou son sel acceptable du point de vue pharmaceutique, en tant qu'un ingrédient actif.
  5. Inhibiteur du FXa caractérisé en ce que l'Inhibiteur contient un composé représenté par la formule (I), ou son sel acceptable du point de vue pharmaceutique, en tant qu'un ingrédient actif.
  6. Composé représenté par la formule (V) ou son sel
    Figure 03360001
    dans laquelle A, B, X, Y, I et m sont tels que définis pour la formule (I) ; le cycle contenant X et le cycle contenant Y sont indépendamment et facultativement substitués ; et R est un atome d'halogène, un groupe alkyle en C1-6, un groupe alkoxy en C1-6 ou un groupe alkyle en C1-6 facultativement substitué par un groupe hydroxyle ou un atome d'halogène, à la condition que deux radicaux R puissent former ensemble un groupe alkyle en C1-6, un groupe alkoxy en C1-6 ou un groupe alkylène en C2-4 facultativement substitué par un groupe hydroxyle ou un atome d'halogène.
  7. Composé représenté par la formule (VI) ou son sel
    Figure 03370001
    dans laquelle A, B, X, Y, Z, T, Q, I, m et n sont tels que définis pour la formule (I) ; le cycle contenant X et le cycle contenant Y sont Indépendamment et facultativement substitués ; la chaíne alkylène qui lie Z lorsque n est 1 ou plus est facultativement substituée ; et R est un atome d'hydrogène, un groupe alkyle en C1-6, un groupe alkoxy en C1-6 ou un groupe alkyle en C1-6 facultativement substitué par un groupe hydroxyle ou un atome d'halogène, à la condition que deux radlcaux R puissent former ensemble un groupe alkyle en C1-6, un groupe alkoxy en C1-6 ou un groupe alkylène en C2-4 facultativement substitué par un groupe hydroxyle ou un atome d'halogène.
  8. Composé représenté par la formule (Ik) ou son sel
    Figure 03370002
    dans laquelle P1 et P2 représentent indépendamment un atome d'hydrogène ou un groupe protégeant le groupe imino ; Y, Z, D, l, m, n et r sont tels que définis pour la formule (I) ; et les trois cycles sont Indépendamment, et facultativement substitués.
  9. Composé représenté par la formule (l-a') ou son sel
    Figure 03380001
    dans laquelle A, B, D, X, Y, Z, Q, T, l, m, n et r sont tels que définis pour la formule (I) ; W est un groupe qui part ou un groupe convertible en un groupe qui part ; le cycle contenant X et le cycle contenant Y sont indépendamment et facultativement substitués ; et le groupe alkylène qui lie Z lorsque n est 1 ou plus est facultativement substitué.
  10. Composé manifestant une activité inhibitrice du FXa qui possède une Cl50 allant jusqu'à 1 µM et une structure partielle représentée par la formule (I") dans sa molécule, ou son sel acceptable du point de vue pharmaceutique :
    Figure 03380002
    dans laquelle -X= est -CH= ou -N= ; les trois cycles (le cycle contenant X, le cycle contenant Y et le cycle contenant Z) sont Indépendamment et facultativement substitués ; Y, Z, D, T, Q, I, m, n et r sont tels que définis pour la formule (I).
  11. Composé manifestant une activité inhibitrice du FXa qui possède une Cl50 allant jusqu'à 1 µM et une structure partielle représentée par la formule (I"') dans sa molécule, ou son sel acceptable du point de vue pharmaceutique :
    Figure 03390001
    dans laquelle X est un groupe méthine ou un atome d'azote ; les trois cycles (le cycle contenant X, le cycle contenant Y et le cycle contenant Z) sont indépendamment et facultativement substitués ; A, B, Y, Z, D, I, m, n et r sont tels que définis pour la formule (I).
  12. Composé manifestant une activité Inhibitrice du FXa représenté par la formule (I') suivante, ou son sel acceptable du point de vue pharmaceutique :
    Figure 03390002
    dans laquelle D est un atome d'hydrogène, -CO-R5 (où R5 est un atome d'hydrogène ou un substituant) ou un groupe alkyle en C1-6 facultativement substitué ;
       X est un groupe méthine ou un atome d'azote ;
       Y est un atome d'oxygène, -S(O)y- ou un groupe imlno (-NH-) facultativement substitué ;
       les trols cycles (le cycle contenant X, le cycle contenant Y et le cycle contenant Z) sont Indépendamment et facultativement substitués ;
       Z est un groupe méthylène, un groupe carbonyle ou un groupe thiocarbonyle ;
       l, m, n et y sont indépendamment un nombre entier choisi parmi 0, 1 et 2, à la condition que 1 et m ne soient pas simultanément 0 ; et r est le nombre entier 0 ou 1 ;
       la liaison indiquée par le trait pointillé et le trait plein est une simple liaison ou une double liaison (lorsque r est 0) ; et
       La et Lb sont des groupes impliqués dans la liaison du composé de formule (I') à FXa, et
       La représente un groupe comportant un fragment basique qui s'associe à la poche S3 de FXa [un espace formé au moins par les résidus d'acide aminé Trp215, Phe174, Tyr99, Thr98, Glu97 et Lys96], et
       Lb représente un groupe comportant un fragment hydrophobe qui lie la poche S1 de FXa [un espace formé par au moins les résidus d'acide aminé Val213, Ser214, Trp215, Gly216, Glu217, Gly218, Cys220, Asp189, Ala190, Cys191, Gln192, Gly193, Asp194, Ser195, Gly226, Ile227 et Tyr228], et qui interagit avec la chaíne latérale du résidu Tyr228 dans la poche S1 mais qui ne Ile pas de manière covaiente le résidu Ser195 dans le centre actif (où le numéro d'acide aminé du FXa est indiqué par le numéro de chymotrypsine utilisé dans la banque de données sur les protéines (Protein Data Bank, PDB), référence: 1 FAX (J. Biol. Chem. 1996, Nov. 22; 271(47): 29988-92)), à la condition que le composé de formule (I') est un composé dans lequel, lorsque la fragment hydrophobe Interagit avec le résidu Tyr228 dans la liaison du composé de formule (I') avec FXa, la distance entre le centroïde (le point de coordonnées obtenu en calculant la moyenne des coordonnées X, Y et Z de tous les atomes lourds Inclus dans la structure partielle ; ci-après simplement appelé le centroïde) du fragment hydrophobe de Lb et le centroïde de la chaïne latérale de Tyr228 soit compris dans l'intervalle de 6,9 à 7,9 Å, et, en outre, le composé est également un composé inhlbant FXa qui satisfait au moins l'une des conditions 1) à 3) suivantes:
    1) lorsque le composé lie FXa, le fragment hydrophobe de Lb ne subit, ni partiellement, ni dans sa totalité, aucune interaction électrostatique avec le résidu Asp189 de la poche S1 ;
    2) lorsque le composé lie FXa, la position du centroïde du fragment hydrophobe de Lb dans la poche S1 satisfait au moins deux des conditions suivantes :
    i) la position est à une distance de 3,6 à 4,6 Å de l'atome Cα du squelette de Cys191 ;
    ii) la position est à une distance de 6,2 à 7,2 Å de l'atome Cα du squelette de Ser195 ;
    iii) la position est à une distance de 5,5 à 6,5 Å de l'atome Cα du squelette de Ser214 ;
    iv) la position est à une distance de 3,6 à 4,6 Å de l'atome Cα du squelette de Trp215 ;
    v) la position à une distance de 6,7 à 7,7 Å de l'atome Cα du squelette de Glu217 ; et
    vi) la position est à une distance de 5,8 à 6,8 Å de l'atome Cα du squelette de Cys220 ;
    3) lorsque le composé lie FXa, la position du centroïde de la structure partielle comprenant le fragment basique de La dans la poche S3 satisfait au moins deux des conditions suivantes :
    I) la position est à une distance de 4,1 à 5,5 Å du centroïde de la chaíne latérale du résidu Tyr99 ;
    II) la position est à une distance de 3,1 à 4,5 Å du centroïde de la chaíne latérale du résidu Phe174 ;
    III) la position est à une distance de 4,1 à 5,5 Å du centroïde de la chaíne latérale du résidu Trp215 ;
    iv) la position à une distance de 4,1 à 6,3 Å de l'atome d'oxygène du carbonyle du squelette Lys96 ;
    v) la position est à une distance de 3,5 à 5,1 Å de l'atome d'oxygène carbonyle du squelette Glu97).
  13. Composition pharmaceutique caractérisée en ce que la composition contlent au moins un composé ou son sel acceptable du point de vue pharmaceutique selon les revendications 10 à 12 en tant qu'un ingrédient actif.
  14. Utilisation d'un composé choisi parml les composés selon la revendication 1, 10, 11 ou 12, ou un sel acceptable du point de vue pharmaceutique de l'un quelconque de ces composés, en vue de la préparation d'un médicament destiné à l'inhibition prophylactique et/ou thérapeutique de FXa chez un mammifère.
  15. Cristal d'un complexe entre Fxa et au moins un composé ou son sel selon les revendications 10 à 12.
EP00940912A 1999-06-30 2000-06-30 Composes tricycliques presentant une jonction spiro Expired - Lifetime EP1191028B1 (fr)

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PCT/JP2000/004374 WO2001002397A1 (fr) 1999-06-30 2000-06-30 Composes tricycliques presentant une jonction spiro

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US20030187023A1 (en) * 2000-07-17 2003-10-02 Keiji Kubo Sulfone derivatives, process for their production and use thereof
CA2433174A1 (fr) * 2000-12-28 2002-07-11 Mochida Pharmaceutical Co., Ltd. Inhibiteurs de la biosynthese du cholesterol contenant comme principe actif des composes spiro tricycliques
DK1569912T3 (en) 2002-12-03 2015-06-29 Pharmacyclics Inc 2- (2-hydroxybiphenyl-3-yl) -1h-benzoimidazole-5-carboxamidine derivatives as factor VIIa inhibitors.
TWI396686B (zh) 2004-05-21 2013-05-21 Takeda Pharmaceutical 環狀醯胺衍生物、以及其製品和用法
WO2006006490A1 (fr) * 2004-07-08 2006-01-19 Ono Pharmaceutical Co., Ltd. Composé spirocyclique
WO2006106804A1 (fr) 2005-03-31 2006-10-12 Mochida Pharmaceutical Co., Ltd. Composé spiro tricyclique comprenant un groupement acyle lié à un atome d'azote de cycle
CA2651420A1 (fr) 2006-05-23 2007-11-29 Mochida Pharmaceutical Co., Ltd. Compose spiro tetracyclique
US7739434B2 (en) 2008-01-11 2010-06-15 International Business Machines Corporation Performing a configuration virtual topology change and instruction therefore

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US5292747A (en) * 1990-08-07 1994-03-08 Hoffman-La Roche Inc. Substituted pyrroles

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EP1191028A4 (fr) 2002-10-23
WO2001002397A9 (fr) 2001-04-05
DE60015541D1 (de) 2004-12-09
TR200103853T2 (tr) 2002-11-21
CZ20014696A3 (cs) 2002-05-15
PL352862A1 (en) 2003-09-08
EP1191028A1 (fr) 2002-03-27
ATE281457T1 (de) 2004-11-15
NO20016402D0 (no) 2001-12-28
IL147348A0 (en) 2002-08-14
JP4890707B2 (ja) 2012-03-07
SK19292001A3 (sk) 2002-06-04
HUP0202188A2 (en) 2002-10-28
AU5572000A (en) 2001-01-22
DE60015541T2 (de) 2005-12-08
BR0012093A (pt) 2002-07-16
HUP0202188A3 (en) 2004-04-28
KR20020015061A (ko) 2002-02-27
CN1371375A (zh) 2002-09-25
NZ516363A (en) 2004-05-28
ZA200110558B (en) 2002-09-12
NO20016402L (no) 2002-02-27
HK1049157A1 (zh) 2003-05-02
MXPA02000003A (es) 2003-07-21
WO2001002397A1 (fr) 2001-01-11
CA2380852C (fr) 2009-10-20
CA2380852A1 (fr) 2001-01-11
AU774397B2 (en) 2004-06-24

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